4,6-SUBSTITUTED-PYRAZOLO[1,5-a]PYRAZINES AS JANUS KINASE INHIBITORS

ABSTRACT

Compounds of Formula I: and stereoisomers and pharmaceutically acceptable salts and solvates thereof in which R 1 , R 2 , R 3  and R 4  have the meanings given in the specification, are inhibitors of one or more JAK kinases and are useful in the treatment of JAK kinase-associated diseases and disorders, such as autoimmune diseases, inflammatory diseases, rejection of transplanted organs, tissues and cells, as well as hematologic disorders and malignancies and their co-morbidities.

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds, and to the use of the compounds in therapy. Moreparticularly, it relates to 4,6-substituted-pyrazolo[1,5-a]pyrazinecompounds which are inhibitors of JAK kinases. In particular, thecompounds are inhibitors of Tyk2, JAK1, JAK2, and/or JAK3, and areuseful in the treatment of JAK kinase-associated diseases such asautoimmune diseases, inflammatory diseases, organ, tissue and celltransplant rejection, and hematological disorders and malignancies.

The members of the Janus kinase (JAK) family of non-receptor,intracellular tyrosine kinases are components of cytokine signaltransduction. Four family members have been identified: JAK1, JAK2, JAK3and Tyk2. The JAKs play a key role in the intracellular signalingmediated through Type I and Type II cytokine receptors. Specificcytokine receptor chains are associated with particular JAK kinases(reviewed in O'Sullivan et al., Mol. Immunol., 2007, 44:2497; Murray J.,Immunol., 2007, 178:2623). Upon binding of cytokines to their receptors,JAKs are activated and phosphorylate the receptors, creating dockingsites for other signaling molecules, in particular members of the signaltransducer and activator of transcription (STAT) family. Uponphosphorylation, STATs dimerize, translocate to the nucleus and activateexpression of genes involved in development, growth, differentiation,and maintenance of a variety of cell types. The cytokine-inducedresponses mediated by JAK kinases are important in host defense and,when dysregulated, play a role in pathogenesis of immune or inflammatorydiseases, immune deficiencies, and malignancy (O'Sullivan et al., Mol.Immunol., 2007, 44:2497). Elevated or decreased levels ofJAK/STAT-utilizing cytokines have been implicated in a number of diseasestates. In addition, mutations or polymorphisms in Type 1 and IIcytokine receptors, JAK kinases, STAT proteins, and JAK/STAT regulatoryproteins such as phosphotyrosine phosphatases, SOCS proteins, PIASproteins have been reported in a variety of diseases. When dysregulated,JAK-mediated responses can positively or negatively affect cells leadingto over-activation and malignancy or immune and hematopoieticdeficiencies, respectively, and suggests the utility for use ofinhibitors of JAK kinases. The JAK/STAT signaling pathway is involved ina variety of hyperproliferative and cancer-related processes includingcell-cycle progression, apoptosis, angiogenesis, invasion, metastasisand evasion of the immune system (Haura et al., Nature Clinical PracticeOncology, 2005, 2(6), 315-324; Verna et al., Cancer and MetastasisReviews, 2003, 22, 423-434). In addition, the JAK/STAT signaling pathwayis important in the genesis and differentiation of hematopoietic cellsand regulating both pro- and anti-inflammatory and immune responses(O'Sullivan et al., Molecular Immunology 2007, 44:2497). Becausecytokines utilize different patterns of JAK kinases (O'Sullivan et al.,Mol. Immunol., 2007, 44:2497; Murray J., Immunol., 2007, 178:2623),there may be utility for antagonists of JAK kinases with differingintra-family selectivity profiles in diseases associated with particularcytokines or in diseases associated with mutations or polymorphisms inthe JAK/STAT pathways.

JAK3 deficient mice exhibit a severe combined immunodeficiency syndrome(scid). The failure of lymphocyte development in an otherwise healthyanimal supports the utility of targeting JAK3 for diseases associatedwith lymphocyte activation.

In addition to the scid phenotype of the JAK3-deficient mice, theelevated expression of cytokines which signal through theJAK3-associated gamma common chain in inflammatory and immune responsessuggests that inhibitors of JAK3 could impede T-cell activation andprevent rejection of grafts following transplant surgery, or to providetherapeutic benefit to patients suffering autoimmune or inflammatorydisorders (reviewed in O'Sullivan et al., Mol. Immunol., 2007, 44:2497;Murray J., Immunol., 2007, 178:2623).

Inhibitors of the tyrosine kinase JAK3 have been described to be usefulas immunosuppressants (see, for example, U.S. Pat. No. 6,313,129; Borieet al., Curr. Opin. Investigational Drugs, 2003, 4:1297). JAK3 has alsobeen shown to play a role in mast-cell mediated allergic reactions andinflammatory diseases.

JAK1-deficient and/or JAK2-deficient animals are not viable. Studieshave identified a high prevalence of an acquired activating JAK2mutation (JAK2V617F) in myleoproliferative disorders such aspolycythemia vera, essential thrombocythemia and idiopathicmyelofibrosis and to a lesser extent in several other diseases. Themutant JAK2 protein is able to activate downstream signaling in theabsence of cytokine stimulation, resulting in autonomous growth and/orhypersensitivity to cytokines and is believed to play a role in drivingthese diseases (Percy, M. J. and McMullin, M. F., HematologicalOncology, 2005, 23(3-4), 91-93). Additional mutations or translocationsresulting dysregulated JAK2 function have been described in othermalignancies (Ihle J. N. and Gilliland D. G., Curr. Opin. Genet. Dev.,2007, 17:8; Sayyah J. and Sayeski P. P., Curr. Oncol. Rep., 2009,11:117). Inhibitors of JAK2 have been described to be useful inmyeloproliferative diseases (Santos et al., Blood, 2010, 115:1131;Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16:129, Atallah E.and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9:663). More rarely,mutations in JAK1 and JAK3 have been reported in hematologicmalignancies (Vainchecker et al., Semin. Cell Dev. Biol., 2008, Aug. 1;9(4):385-93). JAK family kinase inhibitors may be useful in thesesettings (Sayyah J. and Sayeski P. P., Curr. Oncol. Rep., 2009, 11:117).In addition, over expression of cytokines which utilize JAK2 forsignaling have been implicated in disease states (JAK2 utilizingcytokines are reviewed in O'Sullivan et al., Mol. Immunol., 2007,44:2497; Murray J., Immunol., 2007, 178:2623).

JAK1 has been reported to signal with other JAK1 molecules or incollaboration with JAK2 or JAK3 depending on the cytokine input (JAK1utilizing cytokines reviewed in O'Sullivan 2007, Murray 2007). Elevatedlevels of cytokines which signal through JAK1 have been implicated in anumber of immune and inflammatory diseases. JAK1 or JAK family kinaseantagonists may be useful for modulating or treating in such diseases.

Tyk2-deficient animals exhibit blunted immune responses to several typesof pathogens and are less susceptible to some autoimmune diseases. Thisphenotype supports the utility of inhibiting Tyk2 in particular diseasesettings. Particularly, targeting Tyk2 appears to be a promisingstrategy for the treatment of IL-12-, IL-23- or Type 1 IFN-mediateddiseases or diseases. These include but are not limited to rheumatoidarthritis, multiple sclerosis, lupus, psoriasis, psoriatic arthritis,inflammatory bowel disease, uveitis, and sarcoidosis (Shaw, M. et al.,Proc. Natl. Acad. Sci. USA, 2003, 100, 11594-11599; Ortmann, R. A., andShevach, E. M., Clin. Immunol., 2001, 98, 109-118; Watford et al.,Immunol. Rev., 2004, 202:139).

International Publication Nos. WO 2011/130146 (Array BioPharma Inc.) andWO 2013/055645 (Array BioPharma Inc.) disclose 5,7-substitutedimidazo[1,2-c]pyrimidines as inhibitors of one or more JAK kinasesuseful in the treatment of autoimmune diseases, inflammatory diseases,rejection of transplanted organs, tissues and cells, as well ashematologic disorders and malignancies and their co-morbidities.

There remains a need for compounds and methods for the treatment ofautoimmune diseases, inflammatory diseases, organ, tissue and celltransplant rejection, and hematologic disorders and malignancies.

SUMMARY OF THE INVENTION

It has now been found that 4,6-substituted-pyrazolo[1,5-a]pyrazinecompounds are inhibitors of one or more JAK kinases and are useful fortreating JAK kinase-associated diseases and disorders, includingautoimmune diseases, inflammatory diseases, rejection of transplantedorgans, tissues and cells, as well as hematologic disorders andmalignancies and their co-morbidities.

More specifically, provided herein are compounds of General Formula I:

and stereoisomers and pharmaceutically acceptable salts and solvatesthereof, wherein R¹, R², R³ and R⁴ are as defined herein.

Also provided herein are pharmaceutical compositions comprising acompound of the present invention or a pharmaceutically acceptable saltor solvate thereof, and a pharmaceutically acceptable carrier.

Also provided herein are methods of treating a disease or disordermodulated by (i.e., associated with) one or more JAK kinases, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof as defined herein.

In one embodiment, provided herein is a method of treating an autoimmunedisease or inflammatory disease, comprising administering to a subjectin need of such treatment a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof as definedherein.

In one embodiment, provided herein is a method of preventing anautoimmune disease or inflammatory disease, comprising administering toa subject in need of such treatment a therapeutically effective amountof a compound of General Formula I or a pharmaceutically acceptable saltor solvate thereof, or a pharmaceutical composition thereof as definedherein.

In one embodiment, provided herein is a method of treating organ, tissueor cell transplant rejection, comprising administering to a subject inneed of such treatment a therapeutically effective amount of a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof as defined herein.

In one embodiment, provided herein is a method of preventing organ,tissue and cell transplant rejection, comprising administering to asubject in need of such treatment a therapeutically effective amount ofa compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof as definedherein.

In another embodiment, provided herein is a method of treatinghematological disorders and malignancies, comprising administering to asubject in need of such treatment a therapeutically effective amount ofa compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof as definedherein.

Also provided herein are compounds of General Formula I, orpharmaceutically acceptable salts or solvates thereof, or pharmaceuticalcompositions thereof, as defined herein, for use in therapy, e.g., foruse in the treatment of a JAK kinase-associated disease or disorder.

Also provided herein are compounds of General Formula I, orpharmaceutically acceptable salts or solvates thereof, or pharmaceuticalcompositions thereof, as defined herein, for use in the treatment ofautoimmune diseases and inflammatory diseases.

Also provided herein are compounds of General Formula I, orpharmaceutically acceptable salts or solvates thereof, or pharmaceuticalcompositions thereof, as defined herein, for use in the treatment oforgan, tissue and cell transplant rejection.

Also provided herein are compounds of General Formula I, orpharmaceutically acceptable salts or solvates thereof, or pharmaceuticalcompositions thereof, as defined herein, for use in the treatment ofhematological disorders and malignancies.

Also provided herein is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof, in the manufacture of a medicament for thetreatment of a JAK kinase-associated disease or disorder, such asautoimmune diseases, inflammatory diseases, and organ, tissue and celltransplant rejection, and hematological disorders and malignancies.

Also provided herein is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof, in the manufacture of a medicament for thetreatment of hematological disorders and malignancies.

Also provided herein is a method for inhibiting JAK kinase activity in acell, the method comprising contacting the cell with a compound ofFormula I or pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, wherein said contacting is in vitroor in vivo. In one embodiment, the cell is a mammalian cell.

Also provided herein is a pharmaceutical combination for treating a JAKkinase-associated disease or disorder in a subject in need thereof,which comprises (a) a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, (b) an additionaltherapeutic agent, and (c) optionally at least one pharmaceuticallyacceptable carrier, for simultaneous, separate or sequential use for thetreatment of a JAK kinase-associated disorder, wherein the amounts ofthe compound of General Formula I or pharmaceutically acceptable salt orsolvate thereof and the additional therapeutic agent are togethereffective in treating the JAK kinase-associated disease or disorder.Also provided herein is a pharmaceutical composition comprising such acombination. Also provided herein is the use of such a combination forthe preparation of a medicament for the treatment of a JAKkinase-associated disorder. Also provided herein is a commercial packageor product comprising such a combination for simultaneous, separate orsequential use.

Also provided herein are intermediates for preparing compounds ofGeneral Formula I.

Also provided herein are methods of preparing, methods of separation,and methods of purification of the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds, and pharmaceutical compositions thereof,which are useful in the treatment of JAK kinase-associated diseases ordisorders, for example autoimmune diseases, inflammatory diseases,organ, tissue and cell transplant rejection, and hematological disordersand malignancies.

Accordingly, one embodiment of this invention provides a compound of thegeneral Formula I

or a stereoisomer or pharmaceutically acceptable salt or solvatethereof, wherein:

R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—, (1-4Calkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl, H₂N(1-4Calkoxy)(3-6C)alkyl, Cyc¹(CH₂)_(m)—, hetCyc¹, hetCyc²CH₂—,R^(a)R^(b)NC(═O)CH₂—, hetCyc^(3a)(1-3C)alkyl,hetCyc^(3b)(2-3C)hydroxyalkyl, R^(c)R^(d)N(2-3C)alkyl, (1-3Calkyl)₂NSO₂(2-3C)alkyl, hetCyc⁴, (1-6C)alkyl or CH₃SO₂(1-6C)alkyl;

Cyc¹ is a 4-6 membered cycloalkyl substituted with 1-2 substituentsindependently selected from the group consisting of HO, HOCH₂—,(1-3C)alkyl, H₂NHC(═O)—, (1-3C alkyl)₂NC(═O)— and HOCH₂CH₂NHC(═O)—;

m is 0 or 1;

hetCyc¹ is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N, O and S wherein the S is optionally oxidized to SO₂,wherein said heterocyclic ring is optionally substituted with asubstituent selected from the group consisting of OH, (1-3Calkyl)C(═O)—, (1-3C alkyl)SO₂—, (1-3C alkyl)NHC(═O)— and NH₂CH₂C(═O)—;

hetCyc² is a 4-6 membered heterocyclic ring having a ring S atom,wherein the S is oxidized to SO₂;

R^(a) and R^(b) are independently H or (1-3C)alkyl, or

R^(a) and R^(b) together with the nitrogen atom to which they areattached form a 4-6 membered ring optionally having a ring oxygen atom;

hetCyc^(3a) and hetCyc^(3b) are independently a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein said heterocyclic ring is optionally substitutedwith 1-2 substituents independently selected from the group consistingof halogen, OH, (1-4C)alkoxy, HOCH₂—, (1-3C alkyl)C(═O)— and oxo;

R^(c) is H or (1-3C)alkyl;

R^(d) is (1-3C)alkyl, (1-3C alkyl)SO₂—, hetCyc^(a), or (3-6C)cycloalkyloptionally substituted with HOCH₂—;

hetCyc^(a) is a 5-6 membered azacyclic ring optionally substituted with1-2 substituents independently selected from oxo and (1-3C)alkyl;

hetCyc⁴ is azetidinyl substituted with ((CH₃)₂N)₂P(═O)— or Y—C(═O)—;

Y is R^(e)R^(f)N(CH₂)_(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl,(1-3C alkyl)₂NC(═O)—, (1-3C)alkylSO₂- or (1-3C)alkyl;

n is 0 or 1;

R^(e) and R^(f) are independently H or (1-3C)alkyl;

hetCyc^(b) is a 4-5 membered azacyclic ring optionally substituted withOH;

Cyc² is a (3-6C)cycloalkyl optionally substituted with OH;

R² is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl(optionally substituted with one or two halogens), (3-6C)cycloalkylCH₂—,HOC(═O)— or phenyl, and

R³ is (1-6C)alkyl or (3-6C)cycloalkyl, or

R² and R³ together with the carbon atom to which they are attached forma 3-7 membered cycloalkyl ring optionally substituted with one or twosubstituents independently selected from OH, (1-6C)alkyl andhydroxy(1-6C)alkyl, or

R² and R³ together with the carbon atom to which they are attached forma 4-membered saturated azacyclic ring substituted with SO₂CF₃; and

R⁴ is hydrogen or (1-6C)alkyl.

In one embodiment of Formula I, R¹ is hydroxy(1-6C)alkyl. Non-limitingexamples include the structures:

In one embodiment, R¹ is HOCH₂(cyclopropylidine)CH₂— having thestructure:

In one embodiment, R¹ is (hydroxy)trifluoro(1-6C)alkyl, that is, a(1-6C)alkyl as defined herein, wherein one of the hydrogen atoms isreplaced with hydroxy, and three of the hydrogen atoms are replaced byfluorine. A non-limiting example is the structure:

In one embodiment, R¹ is (1-4C alkoxy)(1-6C)hydroxyalkyl, that is, a(1-6C)alkyl as defined herein, wherein one of the hydrogen atoms isreplaced with hydroxy, and one of the hydrogen atoms is replaced with a(1-4C alkoxy) group. A non-limiting example is the structure:

In one embodiment, R¹ is dihydroxy(2-6C)alkyl, that is, a (2-6C)alkyl asdefined herein, wherein two of the hydrogen atoms are replaced with a OHgroup, provided that the two OH groups are not on the same carbon.Non-limiting examples include the structures:

In one embodiment, R¹ is H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl or (1-3C alkyl)₂N(3-6C)hydroxyalkyl, that is,a (3-6C)alkyl group as defined herein, wherein one of the hydrogen atomsis replace with hydroxy, and another hydrogen atom is replaced with anH₂N—, (1-3C alkyl)NH— or (1-3C alkyl)₂N— group, respectively, providedthat the hydroxy group and the amine-containing group are not on thesame carbon. Non-limiting examples include the structures:

In one embodiment, R¹ is H₂N(1-4C alkoxy)(3-6C)alkyl, that is, a(3-6C)alkyl group, wherein one of the hydrogen atoms is replaced with anH₂N— group, and another hydrogen atom is replaced with a (1-4C)alkoxygroup, provided the H₂N— group and (1-4C)alkoxy group are not on thesame carbon. A non-limiting example is the structure:

In one embodiment, R¹ is Cyc¹(CH₂)_(m)—, where m is 0 or 1 and Cyc¹ is a4-6 membered cycloalkyl substituted with 1-2 substituents independentlyselected from the group consisting of HO, HOCH₂—, (1-3C)alkyl,H₂NHC(═O)—, (1-3C alkyl)₂NC(═O)— and HOCH₂CH₂NHC(═O)—. Non-limitingexamples of R¹ when represented by Cyc¹(CH₂)_(m)— include thestructures:

In one embodiment, R¹ is hetCyc¹, where hetCyc¹ is a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N, O and Swherein the S is optionally oxidized to SO₂, wherein said heterocyclicring is optionally substituted with a substituent selected from thegroup consisting of OH, (1-3C alkyl)C(═O)—, (1-3C alkyl)SO₂—, (1-3Calkyl)NHC(═O)— and NH₂CH₂C(═O)—. Non-limiting examples of R¹ whenrepresented by hetCyc¹ include the structures:

In one embodiment, R¹ is hetCyc²CH₂—, where hetCyc² is a 4-6 memberedheterocyclic ring having a ring S atom, wherein the S is oxidized toSO₂. A non-limiting example of R¹ when represented by hetCyc²CH₂—includes the structure:

In one embodiment, R¹ is R^(a)R^(b)NC(═O)CH₂—, where R^(a) and R^(b) areindependently H or (1-3C)alkyl, or R^(a) and R^(b) together with thenitrogen atom to which they are attached form a 4-6 membered ringoptionally having a ring oxygen atom. Non-limiting examples of R¹ whenrepresented by R^(a)R^(b)NC(═O)CH₂— include the structures:

In one embodiment, R¹ is hetCyc^(3a)(1-3C)alkyl (that is, a 1-3C alkylas defined herein, where one of the hydrogen atoms is replaced withhetCyc^(3a)) or hetCyc^(3b)(2-3C)hydroxyalkyl (that is, a 2-3C alkyl asdefined herein, where one hydrogen atom is replaced with hydroxy andanother hydrogen atom is replaced with hetCyc^(3b)), where hetCyc^(3a)and hetCyc^(3b) are independently a 4-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinsaid heterocyclic ring is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, OH,(1-4C)alkoxy, HOCH₂— (1-3C alkyl)C(═O)— and oxo. Non-limiting examplesof R¹ when represented by hetCyc^(3a)(1-3C)alkyl orhetCyc^(3b)(2-3C)hydroxyalkyl include the structures:

In one embodiment, R¹ is hetCyc^(3a)(1-3C)alkyl orhetCyc^(3b)(2-3C)hydroxyalkyl, where hetCyc³ is a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein said heterocyclic ring is substituted with 1-2substituents independently selected from the group consisting ofhalogen, OH, (1-4C)alkoxy, HOCH₂— (1-3C alkyl)C(═O)— and oxo, andhetCyc^(3b) a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein said heterocyclic ring isoptionally substituted with 1-2 substituents independently selected fromthe group consisting of halogen, OH, (1-4C)alkoxy, HOCH₂— (1-3Calkyl)C(═O)— and oxo. Non-limiting examples of R¹ when represented byhetCyc^(3a)(1-3C)alkyl or hetCyc^(3b)(2-3C)hydroxyalkyl include thestructures:

In one embodiment, R¹ is R^(c)R^(d)N(2-3C)alkyl, that is, a (2-3C)alkylas defined herein where one of the hydrogen atoms is replaced with aR^(c)R^(d)N— group, where R^(c) is H or (1-3C)alkyl; R^(d) is(1-3C)alkyl, (1-3C alkyl)SO₂—, hetCyc^(a), or (3-6C)cycloalkyloptionally substituted with HOCH₂—; and hetCyc^(a) is a 5-6 memberedazacyclic ring optionally substituted with 1-2 substituentsindependently selected from oxo and (1-3C)alkyl. Non-limiting examplesof R¹ when represented by R^(c)R^(d)N(2-3C)alkyl include the structures:

In one embodiment, R¹ is (1-3C alkyl)₂NSO₂(2-3C)alkyl, that is, a(2-3C)alkyl as defined herein, wherein one of the hydrogens is replacedwith a (1-3C alkyl)₂NSO₂— group. A non-limiting example is thestructure:

In one embodiment, R¹ is hetCyc⁴, where hetCyc⁴ is an azetidinyl ringsubstituted with ((CH₃)₂N)₂P(═O)—, Y—C(═O)— or (1-3C)alkylSO₂; Y isR^(e)R^(f)N(CH₂)_(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl, (1-3Calkyl)₂NC(═O)— or (1-3C)alkyl; n is 0 or 1; R^(e) and R^(f) areindependently H or (1-3C)alkyl; hetCyc^(b) is a 4-5 membered azacyclicring optionally substituted with OH; and Cyc² is (3-6C)cycloalkyloptionally substituted with OH. Non-limiting examples of R¹ whenrepresented by hetCyc⁴ include the structures:

In one embodiment, R¹ is hetCyc⁴, where hetCyc⁴ is an azetidinyl ringsubstituted with ((CH₃)₂N)₂P(═O)— or Y—C(═O)—; Y isR^(e)R^(f)N(CH₂)_(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl or (1-3Calkyl)₂NC(═O)—; n is 1; R^(e) and R^(f) are independently H or(1-3C)alkyl; hetCyc^(b) is a 4-5 membered azacyclic ring optionallysubstituted with OH; and Cyc² is (3-6C)cycloalkyl substituted with OH.Non-limiting examples of R¹ when represented by hetCyc⁴ include thestructures:

In one embodiment, R¹ is (1-6C)alkyl. In one embodiment, R¹ is methyl.

In one embodiment, R¹ is CH₃SO₂(1-6C)alkyl. In one embodiment, R¹ isCH₃SO₂CH₂CH₂— or CH₃SO₂CH₂CH₂CH₂—.

In one embodiment of General Formula I, R¹ is hydroxy(1-6C)alkyl,HOCH₂(cyclopropylidine)CH₂—, (1-4C alkoxy)(1-6C)hydroxyalkyl,(hydroxy)trifluoro(1-6C)alkyl, dihydroxy(2-6C)alkyl,H₂N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl, (1-3Calkyl)₂N(3-6C)hydroxyalkyl, H₂N(1-4C alkoxy)(3-6C)alkyl, Cyc¹(CH₂)_(m)—,hetCyc¹, hetCyc²CH₂—, R^(a)R^(b)NC(═O)CH₂—, hetCyc^(3a)(1-3C)alkyl,hetCyc³b(2-3C)hydroxyalkyl, R^(c)R^(d)N(2-3C)alkyl, (1-3Calkyl)₂NSO₂(2-3C)alkyl or hetCyc⁴;

Cyc¹ is a 4-6 membered cycloalkyl substituted with 1-2 substituentsindependently selected from the group consisting of HO, HOCH₂—,(1-3C)alkyl, H₂NHC(═O)—, (1-3C alkyl)₂NC(═O)—, and HOCH₂CH₂NHC(═O)—;

m is 0 or 1;

hetCyc¹ is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N, O and S wherein the S is optionally oxidized to SO₂,wherein said heterocyclic ring is substituted with a substituentselected from the group consisting of OH, (1-3C alkyl)C(═O)—, (1-3Calkyl)SO₂—, (1-3C alkyl)NHC(═O)— and H₂NCH₂C(═O)—;

hetCyc² is a 4-6 membered heterocyclic ring having a ring S atom,wherein the S is oxidized to SO₂;

R^(a) and R^(b) are independently H or (1-3C)alkyl, or

R^(a) and R^(b) together with the nitrogen atom to which they areattached form a 4-6 membered ring optionally having a ring oxygen atom;

hetCyc^(3a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is substituted with 1-2 substituents independentlyselected from the group consisting of halogen, OH, (1-4C)alkoxy, HOCH₂—,(1-3C alkyl)C(═O)— and oxo;

hetCyc^(3b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, OH,(1-4C)alkoxy, HOCH₂—, (1-3C alkyl)C(═O)— and oxo;

R^(c) is H or (1-3C)alkyl;

R^(d) is (1-3C)alkyl, (1-3C alkyl)SO₂—, hetCyc^(a), or (3-6C)cycloalkyloptionally substituted with HOCH₂—;

hetCyc⁴ is azetidinyl substituted with ((CH₃)₂N)₂P(═O)— or Y—C(═O)—;

Y is R^(e)R^(f)N(CH₂)_(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl or(1-3C alkyl)₂NC(═O)—;

n is 0 or 1;

R^(e) and R^(f) are independently H or (1-3C)alkyl;

hetCyc^(b) is a 4-5 membered azacyclic ring optionally substituted withOH; and

Cyc² is a (3-6C)cycloalkyl optionally substituted with OH.

In one embodiment of General Formula I, R¹ is hydroxy(1-6C)alkyl,HOCH₂(cyclopropylidine)CH₂—, (1-4C alkoxy)(1-6C)hydroxyalkyl,(hydroxy)trifluoro(1-6C)alkyl, dihydroxy(2-6C)alkyl,H₂N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl, (1-3Calkyl)₂N(3-6C)hydroxyalkyl, H₂N(1-4C alkoxy)(3-6C)alkyl, Cyc¹(CH₂)_(m)—,hetCyc¹, hetCyc²CH₂—, R^(a)R^(b)NC(═O)CH₂₋, hetCyc^(3a)(1-3C)alkyl,hetCyc³b(2-3C)hydroxyalkyl, R^(c)R^(d)N(2-3C)alkyl, (1-3Calkyl)₂NSO₂(2-3C)alkyl or hetCyc⁴;

Cyc¹ is a 4-6 membered cycloalkyl substituted with 1-2 substituentsindependently selected from the group consisting of HO, HOCH₂—,H₂NHC(═O)—, (1-3C alkyl)₂NC(═O)—, and HOCH₂CH₂NHC(═O)—;

m is 0 or 1;

hetCyc¹ is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N, O and S wherein the S is optionally oxidized to SO₂,wherein said heterocyclic ring is substituted with a substituentselected from the group consisting of OH, (1-3C alkyl)C(═O)—, (1-3Calkyl)SO₂—, (1-3C alkyl)NHC(═O)— and H₂NCH₂C(═O)—;

hetCyc² is a 4-6 membered heterocyclic ring having a ring S atom,wherein the S is oxidized to SO₂;

R^(a) and R^(b) are independently H or (1-3C)alkyl, or

R^(a) and R^(b) together with the nitrogen atom to which they areattached form a 4-6 membered ring optionally having a ring oxygen atom;

hetCyc^(3a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is substituted with 1-2 substituents independentlyselected from the group consisting of halogen, OH, (1-4C)alkoxy, HOCH₂—,(1-3C alkyl)C(═O)— and oxo;

hetCyc^(3b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, OH,(1-4C)alkoxy, HOCH₂—, (1-3C alkyl)C(═O)— and oxo;

R^(c) is H or (1-3C)alkyl;

R^(d) is (1-3C)alkyl, (1-3C alkyl)SO₂—, hetCyc^(a), or (3-6C)cycloalkyloptionally substituted with HOCH₂—;

hetCyc⁴ is azetidinyl substituted with ((CH₃)₂N)₂P(═O)— or Y—C(═O)—;

Y is R^(e)R^(f)N(CH₂)_(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl or(1-3C alkyl)₂NC(═O)—;

n is 0 or 1;

R^(e) and R^(f) are independently H or (1-3C)alkyl;

hetCyc^(b) is a 4-5 membered azacyclic ring optionally substituted withOH; and

Cyc² is a (3-6C)cycloalkyl optionally substituted with OH.

In one embodiment of General Formula I, R¹ is hydroxy(1-6C)alkyl,HOCH₂(cyclopropylidine)CH₂—, (1-4C alkoxy)(1-6C)hydroxyalkyl,(hydroxy)trifluoro(1-6C)alkyl, dihydroxy(2-6C)alkyl,H₂N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl, (1-3Calkyl)₂N(3-6C)hydroxyalkyl or H₂N(1-4C alkoxy)(3-6C)alkyl.

In one embodiment of General Formula I, R¹ is dihydroxy(2-6C)alkyl,H₂N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl or (1-3Calkyl)₂N(3-6C)hydroxyalkyl.

In one embodiment of General Formula I, R¹ is dihydroxy(2-6C)alkyl.

Reference will now be made to the portion of Formula I having thestructure:

In one embodiment of General Formula I, R² is (1-6C)alkyl,trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl (optionallysubstituted with one or two halogens), (3-6C)cycloalkylCH₂—, HOC(═O)— orphenyl; R³ is (1-6C)alkyl or (3-6C)cycloalkyl; and R⁴ is hydrogen or(1-6C)alkyl. Non-limiting examples include the structures:

In one embodiment of General Formula I, R² is (1-6C)alkyl; R³ is(1-6C)alkyl; and R⁴ is hydrogen.

In one embodiment of General Formula I, R² and R³ together with thecarbon atom to which they are attached form a 3-7 membered cycloalkylring optionally substituted by one or two groups independently selectedfrom OH, (1-6C)alkyl and hydroxy(1-6C)alkyl; and R⁴ is hydrogen or(1-6C)alkyl. In one embodiment, R⁴ is hydrogen or methyl. Non-limitingexamples include the structures:

In one embodiment of General Formula I, R² and R³ together with thecarbon atom to which they are attached form a 4-membered saturatedazacyclic ring substituted with SO₂CF₃; and R⁴ is hydrogen or(1-6C)alkyl. A non-limiting example is the structure:

In one embodiment, General Formula I comprises compounds of Formula IA,and stereoisomers and pharmaceutically acceptable salts and solvatesthereof, wherein:

R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—, (1-4Calkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl, H₂N(1-4Calkoxy)(3-6C)alkyl, Cyc¹(CH₂)_(m)—, hetCyc¹, hetCyc²CH₂—,R^(a)R^(b)NC(═O)CH₂—, hetCyc^(3a)(1-3C alkyl)-,hetCyc^(3b)(2-3C)hydroxyalkyl, R^(c)R^(d)N(2-3C)alkyl, (1-3Calkyl)₂NSO₂(2-3C)alkyl or hetCyc⁴;

Cyc¹ is a 4-6 membered cycloalkyl substituted with 1-2 substituentsindependently selected from the group consisting of HO, HOCH₂—,(1-3C)alkyl, H₂NHC(═O)—, (1-3C alkyl)₂NC(═O)—, and HOCH₂CH₂NHC(═O)—;

m is 0 or 1;

hetCyc¹ is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N, O and S wherein the S is optionally oxidized to SO₂,wherein said heterocyclic ring is substituted with a substituentselected from the group consisting of OH, (1-3C alkyl)C(═O)—, (1-3Calkyl)SO₂—, (1-3C alkyl)NHC(═O)— and H₂NCH₂C(═O)—;

hetCyc² is a 4-6 membered heterocyclic ring having a ring S atom,wherein the S is oxidized to SO₂;

R^(a) and R^(b) are independently H or (1-3C)alkyl, or

R^(a) and R^(b) together with the nitrogen atom to which they areattached form a 4-6 membered ring optionally having a ring oxygen atom;

hetCyc^(3a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is substituted with 1-2 substituents independentlyselected from the group consisting of halogen, OH, (1-4C)alkoxy, HOCH₂—,(1-3C alkyl)C(═O)— and oxo;

hetCyc^(3b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, OH,(1-4C)alkoxy, HOCH₂—, (1-3C alkyl)C(═O)— and oxo;

R^(c) is H or (1-3C)alkyl;

R^(d) is (1-3C)alkyl, (1-3C alkyl)SO₂—, hetCyc^(a), or (3-6C)cycloalkyloptionally substituted with HOCH₂—;

hetCyc^(a) is a 5-6 membered azacyclic ring optionally substituted with1-2 substituents independently selected from oxo and (1-3C)alkyl;

hetCyc⁴ is azetidinyl substituted with ((CH₃)₂N)₂P(═O)— or Y—C(═O)—;

Y is R^(e)R^(f)N(CH₂)_(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl or(1-3C alkyl)₂NC(═O)—;

n is 0 or 1;

R^(e) and R^(f) are independently H or (1-3C)alkyl;

hetCyc^(b) is a 4-5 membered azacyclic ring optionally substituted withOH;

Cyc² is a (3-6C)cycloalkyl optionally substituted with OH;

R² is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl(optionally substituted with one or two halogens), (3-6C)cycloalkylCH₂—,HOC(═O)— or phenyl, and

R³ is (1-6C)alkyl or (3-6C)cycloalkyl, or

R² and R³ together with the carbon atom to which they are attached forma 3-7 membered cycloalkyl ring optionally substituted by one or twogroups independently selected from OH, (1-6C)alkyl andhydroxy(1-6C)alkyl, or

R² and R³ together with the carbon atom to which they are attached forma 4-membered saturated azacyclic ring substituted with SO₂CF₃; and

R⁴ is hydrogen or (1-6C)alkyl.

In one embodiment of Formula IA, R¹ is dihydroxy(2-6C)alkyl.

In one embodiment, General Formula I comprises compounds of Formula IB,and stereoisomers and pharmaceutically acceptable salts and solvatesthereof, wherein:

R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—, (1-4Calkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl or H₂N(1-4Calkoxy)(3-6C)alkyl;

R² is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl(optionally substituted with one or two halogens), (3-6C)cycloalkylCH₂—,HOC(═O)— or phenyl, and

R³ is (1-6C)alkyl or (3-6C)cycloalkyl, or

R² and R³ together with the carbon atom to which they are attached forma 3-7 membered cycloalkyl ring optionally substituted by one or twogroups independently selected from OH, (1-6C)alkyl andhydroxy(1-6C)alkyl, or

R² and R³ together with the carbon atom to which they are attached forma 4-membered saturated azacyclic ring substituted with SO₂CF₃; and

R⁴ is hydrogen or (1-6C)alkyl.

In one embodiment of Formula IB, R¹ is dihydroxy(2-6C)alkyl.

In one embodiment of Formula IB, R² is (1-6C)alkyl, R³ is (1-6C)alkyl,and R⁴ is hydrogen.

In one embodiment of Formula IB, R¹ is dihydroxy(2-6C)alkyl, R² is(1-6C)alkyl, R³ is (1-6C)alkyl, and R⁴ is hydrogen.

In one embodiment, General Formula I comprises compounds of Formula IC,and stereoisomers and pharmaceutically acceptable salts and solvatesthereof, wherein:

R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—, (1-4Calkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl or H₂N(1-4Calkoxy)(3-6C)alkyl;

R² is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl(optionally substituted with one or two halogens), (3-6C)cycloalkylCH₂—,HOC(═O)— or phenyl;

R³ is (1-6C)alkyl or (3-6C)cycloalkyl; and

R⁴ is hydrogen or (1-6C)alkyl.

In one embodiment of Formula IC, R¹ is dihydroxy(2-6C)alkyl.

In one embodiment of Formula IC, R² is (1-6C)alkyl, R³ is (1-6C)alkyl,and R⁴ is hydrogen.

In one embodiment of Formula IC, R¹ is dihydroxy(2-6C)alkyl, R² is(1-6C)alkyl, R³ is (1-6C)alkyl, and R⁴ is hydrogen.

In one embodiment, General Formula I comprises compounds of Formula ID,and stereoisomers and pharmaceutically acceptable salts and solvatesthereof, wherein:

R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—, (1-4Calkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl, H₂N(1-4Calkoxy)(3-6C)alkyl, Cyc¹(CH₂)_(m)—, hetCyc¹, hetCyc²CH₂—,R^(a)R^(b)NC(═O)CH₂—, hetCyc^(3a)(1-3C alkyl)-,hetCyc^(3b)(2-3C)hydroxyalkyl, R^(c)R^(d)N(2-3C)alkyl, (1-3Calkyl)₂NSO₂(2-3C)alkyl or hetCyc⁴;

Cyc¹ is a 4-6 membered cycloalkyl substituted with 1-2 substituentsindependently selected from the group consisting of HO, HOCH₂—,H₂NHC(═O)—, (1-3C alkyl)₂NC(═O)— and HOCH₂CH₂NHC(═O)—;

m is 0 or 1;

hetCyc¹ is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N, O and S wherein the S is optionally oxidized to SO₂,wherein said heterocyclic ring is substituted with a substituentselected from the group consisting of OH, (1-3C alkyl)C(═O)—, (1-3Calkyl)SO₂—, (1-3C alkyl)NHC(═O)— and H₂NCH₂C(═O)—;

hetCyc² is a 4-6 membered heterocyclic ring having a ring S atom,wherein the S is oxidized to SO₂;

R^(a) and R^(b) are independently H or (1-3C)alkyl, or

R^(a) and R^(b) together with the nitrogen atom to which they areattached form a 4-6 membered ring optionally having a ring oxygen atom;

hetCyc^(3a) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is substituted with 1-2 substituents independentlyselected from the group consisting of halogen, OH, (1-4C)alkoxy, HOCH₂—,(1-3C alkyl)C(═O)— and oxo;

hetCyc^(3b) is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, OH,(1-4C)alkoxy, HOCH₂—, (1-3C alkyl)C(═O)— and oxo;

R^(c) is H or (1-3C)alkyl;

R^(d) is (1-3C)alkyl, (1-3C alkyl)SO₂—, hetCyc^(a), or (3-6C)cycloalkyloptionally substituted with HOCH₂—;

hetCyc^(a) is a 5-6 membered azacyclic ring optionally substituted with1-2 substituents independently selected from oxo and (1-3C)alkyl;

hetCyc⁴ is azetidinyl substituted with ((CH₃)₂N)₂P(═O)— or Y—C(═O)—;

Y is R^(e)R^(f)N(CH₂)_(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl or(1-3C alkyl)₂NC(═O)—;

n is 0 or 1;

R^(e) and R^(f) are independently H or (1-3C)alkyl;

hetCyc^(b) is a 4-5 membered azacyclic ring optionally substituted withOH;

Cyc² is a (3-6C)cycloalkyl optionally substituted with OH;

R² is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl(optionally substituted with one or two halogens), (3-6C)cycloalkylCH₂—,HOC(═O)— or phenyl, and

R³ is (1-6C)alkyl or (3-6C)cycloalkyl, or

R² and R³ together with the carbon atom to which they are attached forma 3-7 membered cycloalkyl ring optionally substituted by one or twogroups independently selected from OH, (1-6C)alkyl andhydroxy(1-6C)alkyl, or

R² and R³ together with the carbon atom to which they are attached forma 4-membered saturated azacyclic ring substituted with SO₂CF₃; and

R⁴ is hydrogen or (1-6C)alkyl.

In one embodiment of Formula ID, R¹ is dihydroxy(2-6C)alkyl.

In one embodiment of Formula ID, R² is (1-6C)alkyl, R³ is (1-6C)alkyl,and R⁴ is hydrogen.

In one embodiment of Formula ID, R¹ is dihydroxy(2-6C)alkyl, R² is(1-6C)alkyl, R³ is (1-6C)alkyl, and R⁴ is hydrogen.

In one embodiment, General Formula I comprises compounds of Formula IE,and stereoisomers and pharmaceutically acceptable salts and solvatesthereof, wherein:

R¹ is Cyc¹(CH₂)_(m)— or (1-6C)alkyl;

Cyc¹ is a 4-6 membered cycloalkyl substituted with 1-2 substituentsindependently selected from the group consisting of (1-3C)alkyl;

m is 0 or 1;

R² is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl(optionally substituted with one or two halogens), (3-6C)cycloalkylCH₂—,HOC(═O)— or phenyl, and

R³ is (1-6C)alkyl or (3-6C)cycloalkyl, or

R² and R³ together with the carbon atom to which they are attached forma 3-7 membered cycloalkyl ring optionally substituted with one or twosubstituents independently selected from OH, (1-6C)alkyl andhydroxy(1-6C)alkyl, or

R² and R³ together with the carbon atom to which they are attached forma 4-membered saturated azacyclic ring substituted with SO₂CF₃; and

R⁴ is hydrogen or (1-6C)alkyl.

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated as a mixture of isomers such as a racemic ordiastereomeric mixture, or in an enantiomerically or diastereomericallypure form. It is intended that all stereoisomeric forms of the compoundsof the invention, including but not limited to, diastereomers,enantiomers and atropisomers, as well as mixtures thereof such asracemic mixtures, form part of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

When words are used to describe a substituent, the rightmost-describedcomponent of the substituent is the component that has the free valence.To illustrate, (1-4C alkoxy)(1-6C)alkyl refers to an alkyl radical,wherein the radical is on the first carbon atom of (1-6C) alkyl group asshown. An example is 2-methoxyethyl, which can be represented by thestructure:

As used herein, the word “a” before a noun represents one or more of theparticular noun.

The terms “(1-3C)alkyl”, “(2-3C)alkyl”, “(1-4C)alkyl”, “(1-6C)alkyl”,“(2-6C)alkyl” and “(3-6C)alkyl” as used herein refers to saturatedlinear or branched-chain monovalent hydrocarbon radicals of one to threecarbon atoms, two to three carbon atoms, one to four carbon atoms, oneto six carbon atoms, two to six carbon atoms, and three to six carbonatoms, respectively. Examples include, but are not limited to, methyl,ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl,2-methyl-2-propyl, pentyl, and hexyl.

The term “(1-6C)alkoxy”, as used herein refer to saturated linear orbranched-chain monovalent alkoxy radicals of one to six carbon atoms,respectively, wherein the radical is on the oxygen atom. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

The terms “trifluoro(1-6C)alkyl”, “difluoro(1-6C)alkyl” and“fluoro(1-6C)alkyl” as use herein refer to saturated linear orbranched-chain monovalent radicals of one to six carbon atoms, whereinthree of the hydrogen atoms are replaced by three, two or one fluorineatoms, respectively. Examples include trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 2,2-difluoroethyl.

In instances where the term “heterocycle” is used, the term is intendedto refer to a saturated heterocyclic ring.

It will also be appreciated that certain compounds of General Formula Imay be used as intermediates for the preparation of further compounds ofGeneral Formula I.

The compounds of General Formula I include salts thereof. In certainembodiments, the salts are pharmaceutically acceptable salts. Inaddition, the compounds of General Formula I include other salts of suchcompounds which are not necessarily pharmaceutically acceptable salts,and which may be useful as intermediates for preparing and/or purifyingcompounds of Formula I and/or for separating enantiomers of compounds ofGeneral Formula I. Particular examples of salts include trifluoroaceticacid salts and hydrochloric acid salts.

The term “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The term “JAK kinase-associated disease or disorder” as used hereinrefers to diseases or disorders associated with aberrant JAK kinaseactivity (including overexpression or mutation of the kinase), anddiseases mediated by JAK kinase involved signaling pathways.Non-limiting example of a JAK kinase-associated diseases and disordersinclude any of the disorders described herein.

The terms “JAK kinase” and “JAK kinases” refer to the four familymembers of the Janus kinase (JAK) family of non-receptor, intracellulartyrosine kinases, i.e., Tyk2, JAK1, JAK2, and JAK3.

As used herein, the term “inhibitor of JAK kinases” when used inreference to a compound of General Formula I, means that a compound ofGeneral Formula I is an inhibitor of one or more of Tyk2, JAK1, JAK2,and/or JAK3.

It will further be appreciated that compounds of General Formula I andtheir salts may be isolated in the form of solvates, and accordingly anysuch solvate is included within the scope of the present invention. Forexample, compounds of General Formula I and their salts can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like.

Compounds of General Formula I may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. That is, an atom, in particular when mentioned in relation toa compound according to General Formula I, comprises all isotopes andisotopic mixtures of that atom, either naturally occurring orsynthetically produced, either with natural abundance or in anisotopically enriched form. For example, when hydrogen is mentioned, itis understood to refer to ¹H, ²H, ³H or mixtures thereof; when carbon ismentioned, it is understood to refer to ¹¹C, ¹²C, ¹³C, ¹⁴C or mixturesthereof; when nitrogen is mentioned, it is understood to refer to ¹³N,¹⁴N, ¹⁵N or mixtures thereof; when oxygen is mentioned, it is understoodto refer to ¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluorois mentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof.Compounds of General Formula I therefore also include compounds with oneor more isotopes of one or more atom, and mixtures thereof, includingradioactive compounds, wherein one or more non-radioactive atoms hasbeen replaced by one of its radioactive enriched isotopes. Radiolabeledcompounds are useful as therapeutics, research reagents, e.g., assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of General Formula I, whetherradioactive or not, are intended to be encompassed within the scope ofthe present invention.

The compounds of General Formula I also include the compounds ofExamples 1-218 described herein, and pharmaceutically acceptable saltsand solvates thereof. In one embodiment, the compounds of GeneralFormula I are selected from the group consisting of the free base of thecompounds of Examples 1-218, the trifluoroacetic acid salts of thecompounds of Examples 1-218, and the hydrochloric acid salts of thecompounds of Examples 1-218.

The present invention further provides a process for the preparation ofa compound of General Formula I or a pharmaceutically acceptable saltthereof as defined herein which comprises:

(a) reacting a corresponding compound having the formula II:

where R², R³ and R⁴ is as defined for General Formula I, and R^(t) andR^(u) are H or (1-6C)alkyl, or R^(t) and R^(u) together with the atomsto which they are connected form a 5-6 membered ring optionallysubstituted with 1-4 substituents selected from (1-3C alkyl), with acorresponding compound having the formula III

where R¹ is as defined for General Formula I and L¹ is halogen, an alkylsulfonate group, an aryl sulfonate group, or a triflate group, in thepresence of a palladium catalyst and a base and optionally in thepresence of a ligand; or

(b) for a compound of General Formula I where R¹ is (1-6C)alkyl,hydroxy(1-6C)alkyl, hetCyc¹, hetCyc²CH₂—, R^(a)R^(b)NC(═O)CH₂₋,hetCyc^(3a)(1-3C alkyl)-, R^(c)R^(d)N(2-3C alkyl)-, (1-3Calkyl)₂NSO₂(2-3C alkyl)- or CH₃SO₂(1-6C)alkyl, reacting a correspondingcompound having the formula IV

where R², R³ and R⁴ are as defined for General Formula I, with(1-6C)alkyl-L², hydroxy(1-6C)alkyl-L², hetCyc¹-L², hetCyc²CH₂-L²,R^(a)R^(b)NC(═O)CH₂-L², hetCyc^(3a)(1-3C alkyl)-L², R^(c)R^(d)N(2-3Calkyl)-L², (1-3C alkyl)₂NSO₂(2-3C alkyl)-L² or CH₃SO₂(1-6C)alkyl-L² andL² is halogen, an alkyl sulfonate group or an aryl sulfonate group, inthe presence of a base, where hetCyc¹, R^(a), R^(b), hetCyc^(3a), R^(c),and R^(d) are as defined for Formula I; or

(c) for a compound of General Formula I where R¹ isdihydroxy(2-6C)alkyl, reacting a reacting a corresponding compoundhaving the formula IV

where R², R³ and R⁴ are as defined for Formula I, with a compound havingthe formula V, VI or VII

where each R¹ is methyl, R^(v), R^(w) and R^(x) are independently H ormethyl, and L³ is a halogen, an alkyl sulfonate group or an arylsulfonate group, in the presence of a base, followed by treatment withhydrochloric acid; or

(d) for a compound of General Formula I where R¹ is H₂NCH₂CH(OH)CH₂—,reacting a corresponding compound having the formula VIII

where R², R³ and R⁴ are as defined for General Formula I, with a base;or

(e) for a compound of General Formula I where R¹ is (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl, orhetCyc^(3b)(2-3C)hydroxyalkyl-, where hetCyc^(3b) is a 4-6 memberedheterocyclic ring having a ring nitrogen atom, wherein said heterocyclicring is optionally substituted with 1-2 substituents independentlyselected from the group consisting of halogen or (1-4C)alkoxy, reactinga corresponding compound having the formula IX

where R², R³ and R⁴ are as defined for General Formula I, with a reagenthaving the formula (1-3C alkyl)NH₂, (1-3C alkyl)₂NH or

where R^(y) and R^(z) are independently selected from the groupconsisting of halogen or (1-4C)alkoxy and hetCyc^(3b) is is a 4-6membered heterocyclic ring having a ring nitrogen atom, wherein saidheterocyclic ring is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen or(1-4C)alkoxy; or

(f) for a compound of General Formula I where R¹ is hydroxy(1-6C)alkyl,(hydroxy)trifluoro(1-6C)alkyl or (1-4C alkoxy)(1-6C)hydroxyalkyl,reacting a corresponding compound having the formula X

where R², R³ and R⁴ are as defined for General Formula I, with a reagenthaving the formula

where G is (1-4C)alkyl, trifluoro(1-4C)alkyl or (1-4Calkoxy)(1-4C)alkyl; or

(g) for a compound of General Formula I where R¹ is

reacting a corresponding compound having the formula XI

where R², R³ and R⁴ are as defined for General Formula I and R^(1a) is

respectively, with a reducing agent; or

(h) for a compound of Formula I where R¹ is hydroxy(1-6C)alkyl, reactinga corresponding compound wherein the hydroxy(1-6C)alkyl is protected asan alkyl ester with a base; or

(i) for a compound of General Formula I where R¹ is R^(c)R^(d)N(CH₂CH₂)—or hetCyc^(3a)(CH₂CH₂)—, where R^(c), R^(d), and hetCyc^(3a) are asdefined for General Formula I, reacting a corresponding compound havingthe formula XII

where R², R³ and R⁴ are as defined for General Formula I and L⁴ is ahalogen an alkyl sulfonate group or an aryl sulfonate group, with areagent having the formula R^(c)R^(d)NH₂ or

where hetCyc^(3a) is as defined for General Formula I; or

(j) for a compound of General Formula I where R¹ is H₂NCH₂CH(OCH₃)CH₂—,reacting a corresponding compound having the formula XIII

where R², R³ and R⁴ are as defined for General Formula I, withhydrazine; or

(k) for a compound of Formula I where R¹ is

reacting a corresponding compound having the formula XIV

where R², R³ and R⁴ are as defined for General Formula I, with anoxidizing agent; or

(l) for a compound of General Formula I where R¹ is Cyc¹(CH₂)_(m)—, Cyc¹is a 4-6 membered cycloalkyl substituted with H₂NHC(═O)— or (1-3Calkyl)₂NC(═O)—, and m is 0, reacting a corresponding compound of GeneralFormula I where R¹ is Cyc¹(CH₂)_(m)—, Cyc¹ is a 4-6 membered cycloalkylsubstituted with CH₃C(═O)O— and m is 0 with ammonia or (1-3C alkyl)NH;or

(m) for a compound of General Formula I wherein R² and R³ form a4-membered azacyclic ring substituted with SO₂CF₃, and R¹ and R⁴ are asdefined for General Formula I, reacting a compound having the formulaXIV

where R¹ and R⁴ are as defined for General Formula I, withtrifluoromethanesulfonic anhydride in the presence of a base; and

optionally removing any protecting groups and optionally preparing apharmaceutically acceptable salt thereof.

In the above processes (a), (b), (c), and (i), an example of an alkylsulfonate includes methyl sulfonate, and an examples of an arylsulfonate is a 4-toluenesulfonate group (i.e., a tosyl group).

Referring to process (a), suitable palladium catalysts includePd₂(dba)₃, Pd(OAc)₂, Pd(PPh₃)₂Cl₂, P(Cy)₃, PdCl₂(dppf) complex withCH₂Cl₂, and Pd(PPh₃)₄. Suitable ligands include XPHOS(dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), DIPHOS(1,2-Bis(diphenylphosphino)ethane or rac-BINAP(racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl). The base may be,for example, an alkali metal carbonate, hydroxide, alkoxide or acetate,such as for example cesium carbonate, sodium carbonate, potassiumcarbonate, sodium hydroxide, sodium tert-butoxide or potassium acetate.Convenient solvents include aprotic solvents such as ethers (for exampletetrahydrofuran or p-dioxane), toluene, DMF or DME. The reaction can beconveniently performed at a temperature ranging from ambient temperatureto 120° C., for example from 80 to 110° C.

Referring to process (b), the base may be, for example, an alkali metalhydride or carbonate, such as sodium hydride, potassium hydride, sodiumcarbonate, potassium carbonate or cesium carbonate. Suitable solventsinclude aprotic solvents such as dimethylacetamide (DMA).

Referring to process (c), the base may be, for example, an alkali metalhydride or carbonate, such as sodium hydride, potassium hydride, sodiumcarbonate, potassium carbonate or cesium carbonate. Suitable solventsinclude aprotic solvents such as ethers (for example tetrahydrofuran orp-dioxane), DMF or DME.

Referring to process (d), suitable bases include alkali metal hydroxidessuch as lithium hydroxide. Suitable solvents include aprotic solventssuch as ethers (for example tetrahydrofuran or p-dioxane), toluene orDMF.

Referring to process (g), suitable reducing agents include sodiumborohydride, diisobutylaluminum hydride and lithium aluminum hydride.

Referring to process (h), the base may be, for example, an alkali metalhydride or carbonate, such as sodium hydride, potassium hydride, sodiumcarbonate, potassium carbonate or cesium carbonate.

Referring to process (k), suitable oxidizing agents includeN-methylmorpholine-N-oxide in combination with osmium tetraoxide.

Referring to process (m), suitable bases include amine bases, such asdiisopropylethylamine (DIEA) or triethylamine. Suitable solvents includeneutral solvents such as dichloromethane and dichloroethane. Thereaction is conveniently performed at temperatures between 0° C. andambient temperature.

Amine groups in compounds described in any of the above methods may beprotected with any convenient amine protecting group. Examples of amineprotecting groups include acyl and alkoxycarbonyl groups, such ast-butoxycarbonyl (Boc), and [2-(trimethylsilyl)ethoxy]methyl (SEM).Likewise, carboxyl groups may be protected with any convenient carboxylprotecting group. Examples of carboxyl protecting groups include(1-6C)alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groupsmay be protected with any convenient alcohol protecting group. Examplesof alcohol protecting groups include benzyl, trityl, silyl ethers, andthe like.

The compounds of formulas III, IV, VIII, IX, X, XI, XII, XIII, XIV andXV, which are useful as intermediates for the preparation of compoundsof General Formula I, are also provided as further aspects of theinvention.

The compounds of General Formula I represent novel inhibitors of one ormore JAK kinases. In particular, the compounds are inhibitors of Tyk2,JAK1, JAK2, and/or JAK3, and are useful in the treatment of cytokine orJAK kinase-associated diseases such as autoimmune diseases, inflammatorydiseases, rejection of transplanted organs, tissues and cells, andhematologic disorders and malignancies and their co-morbidities.

The ability of compounds of the invention to act as inhibitors of Tyk2may be demonstrated by the assay described in Example A.

The ability of compounds of the invention to act as inhibitors of JAK1may be demonstrated by the assay described in Example B.

The ability of compounds of the invention to act as inhibitors of JAK2may be demonstrated by the assay described in Example C.

The ability of compounds of the invention to act as inhibitors of JAK3may be demonstrated by the assay described in Example D.

Compounds of General Formula I may be useful in the treatment of JAKkinase-associated diseases and disorders, such as autoimmune diseasesand inflammatory diseases. Accordingly, provided herein is a method oftreating a JAK kinase-associated disease or disorder in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof, or a pharmaceutical composition thereof. Alsoprovided herein is a method of preventing a JAK kinase-associateddisease or disorder in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of General Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof. In one non-limitingembodiment, the autoimmune disease or inflammatory disease is selectedfrom the group:

(i) arthritis, including rheumatoid arthritis, juvenile arthritis,psoriatic arthritis, reactive arthritis, ankylosing spondylitis,osteoarthritis, and seronegative arthopathies;

(ii) intestinal inflammations including Crohn's disease, ulcerativecolitis, inflammatory bowel disease, celiac diseases, proctitis, andeosinophilic gastroenteritis;

(iii) airways diseases including asthma and other obstructive airwaydiseases, including severe refractory asthma, chronic asthma, airwayhyper-responsiveness, bronchitis, allergic asthma, and chronicobstruction pulmonary disease;

(iv) allergic reactions including severe allergic reaction (includinganaphylaxis);

(v) eye diseases, disorders or conditions including autoimmune diseasesof the eye, uveitis including uveitis associated with Behcet's disease,lens-induced uveitis and optic neuritis;

(vi) skin diseases, conditions or disorders including psoriasis, atopicdermatitis, severe dermatitis, eczema, scleroderma, pruritus and otherpruritic conditions, alopecia areata and mastocytosis;

(vii) sepsis, systemic inflammatory response syndrome, and neutropenicfever;

(viii) fibrosis, including hepatic fibrosis, idiopathic pulmonaryfibrosis, myelofibrosis and scleroderma;

(ix) gout (resolution of tophi);

(x) lupus (also known as systemic lupus erythematosus), includingmanifestations such as cutaneous lupus, lupus nephritis, neurosychiatriclupus and other manifestations;

(xi) neurodegenerative diseases including demyelinating diseases, suchas multiple sclerosis, motor neuron disease, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, and ischemicreperfusion injury in stroke;

(xii) diabetes, including Type I diabetes and complications fromdiabetes, metabolic syndrome and obesity;

(xiii) axial spondyloarthorpathy (axial SpA); and

(xiv) Interferon type 1 activation disorders such as systemic lupuserythematosus, Aicardi-Goutieres syndrome, myositis, and periodontitis.

Additional examples of autoimmune diseases and inflammatory diseasesinclude nephropathy, sarcoidosis, pancreatitis, autoimmune thyroiditis,fibromyalgia, atherosclerosis, autoimmune hemolytic anemia, autoimmuneatrophic gastritis of pernicious anemia, autoimmune encephalomyelitis,autoimmune orchitis, Goodpasture's disease, autoimmune myocarditis,autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis,Graves' disease, primary biliary cirrhosis, chronic aggressivehepatitis, membranous glomerulopathy, Sjogren's syndrome, Reiter'ssyndrome, systemic sclerosis, polyarteritis nodosa, bullous pemphigoid,Cogan's syndrome, Wegener's granulomatosis, cystic fibrosis, mixedconnective tissue disease, antiphospholipid syndrome, polymyositis,dermatomyositis, membranous nephritis, primary sclerosing cholangitis,severe chronic urticaria, giant cell arteritis, eosinophilicesophagitis, and eosinophilic gastritis.

In one embodiment, provided herein is a method of treating autoimmune orinflammatory disease in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of General Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof, wherein the disease ordisorder is selected from (i) arthritis, including rheumatoid arthritis,juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosingspondylitis, osteoarthritis, and seronegative arthopathies; (ii)intestinal inflammations including Crohn's disease, ulcerative colitis,inflammatory bowel disease, celiac diseases, proctitis, and eosinophilicgastroenteritis; (vi) skin diseases, conditions or disorders includingpsoriasis, atopic dermatitis, severe dermatitis, eczema, scleroderma,pruritus and other pruritic conditions, alopecia areata andmastocytosis; and (x) lupus (also known as systemic lupuserythematosus), including manifestations such as cutaneous lupus, lupusnephritis, neurosychiatric lupus and other manifestations.

In one embodiment, provided herein is a method of treating an autoimmuneor inflammatory disease in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of General Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof, wherein the disease ordisorder is selected from lupus, psoriasis, psoriatic arthritis,rheumatoid arthritis, multiple sclerosis and inflammatory boweldiseases.

In one embodiment, provided herein is a method of preventing diseasesand disorders in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound of GeneralFormula I (e.g., any of the exemplary compounds described herein), or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof, wherein the disease or disorder is selected from:

(i) arthritis, including rheumatoid arthritis, juvenile arthritis,psoriatic arthritis, reactive arthritis, ankylosing spondylitis,osteoarthritis, and seronegative arthopathies;

(ii) intestinal inflammations including Crohn's disease, ulcerativecolitis, inflammatory bowel disease, celiac diseases, proctitis, andeosinophilic gastroenteritis;

(vi) skin diseases, conditions or disorders including psoriasis, atopicdermatitis, severe dermatitis, eczema, scleroderma, pruritus and otherpruritic conditions, alopecia areata and mastocytosis; and

(x) lupus (also known as systemic lupus erythematosus), includingmanifestations such as cutaneous lupus, lupus nephritis, neurosychiatriclupus and other manifestations.

Compounds of General Formula I may also be useful for treating organ,tissue or cell transplant rejections, including bone marrow transplant,and in the treatment of autoimmune and inflammatory diseases and ofcomplications arising therefrom in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of atleast one compound of Formula I (e.g., any of the exemplary compoundsdescribed herein) or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof.

Accordingly, provided herein is a method of treating organ, tissue orcell transplant rejection in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of atleast one compound of General Formula I (e.g., any of the exemplarycompounds described herein) or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof.

Also provided herein is a method of preventing organ, tissue or celltransplant rejection in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of atleast one compound of General Formula I (e.g., any of the exemplarycompounds described herein) or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof.

Compounds of Formula I may also be useful in treating certainmalignancies, including solid tumors, skin cancer (e.g., melanoma), andhematological malignancies such as lymphomas and leukemias, and furthermay be useful in treating the complications thereof, including sequelaeof hematologic malignancies (for example, in the treatment ofsplenomegaly in myelofibrosis), as well as cachexia in patients withsolid tumors.

Accordingly, provided herein is a method of treating malignancies in asubject, which comprises administering to said subject a therapeuticallyeffective amount of a compound of Formula I (e.g., any of the exemplarycompounds described herein) or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof. In oneembodiment, the malignancies are selected from solid tumors, skin cancer(e.g., melanoma), and hematological malignancies.

In some embodiments, provided herein is a method for treating a subjectdiagnosed with a JAK kinase-associated disorder (e.g., a JAKkinase-associated disorder as described herein), comprisingadministering to the subject a therapeutically effective amount of acompound of General Formula I (e.g., any of the exemplary compoundsdescribed herein), or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof.

In some embodiments, the compounds of the present invention are usefulfor treating a JAK-associated disease (e.g., a JAK kinase-associateddisorder as described herein) in combination with one or more additionaltherapeutic agents or therapies that work by the same or a differentmechanism of action.

In some embodiments, the additional therapeutic agent is selected fromthe group of: cyclosporin A (e.g. Sandimmune® or Neoral®), rapamycin,FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®, azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3(e.g. Orthocolone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen,piroxicam, antiinflammatory steroids (e.g. prednisolone ordexamethasone), methotrexate, statins, anti-TNF agents (e.g., Enbrel®(etanercept) or Humira® (adalimumab)), Orencia® (abatacept),cyclophosphamide, mycophenolic acid, hydroxychloroquine, and metformin.

In some embodiments, the additional therapeutic agent is selected fromthe group: mitotic inhibitors, alkylating agents, anti-metabolites,antisense DNA or RNA, intercalating antibiotics, growth factorinhibitors, signal transduction inhibitors, cell cycle inhibitors,enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, cytostatic agents anti-androgens, targetedantibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferaseinhibitors.

In some embodiments, the additional therapeutic agent or therapy issurgery or radiotherapy, including, e.g., radioiodide therapy,external-beam radiation, and radium 223 therapy.

In some embodiments, provided herein is a method of treating a JAKkinase-associated disease or disorder (e.g., a disease or disorder asdescribed herein) in a subject in need thereof, comprising administeringto said subject a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof, or a pharmaceutical composition thereof, incombination with at least one additional therapy or therapeutic agentselected from cyclosporin A (e.g. Sandimmune® or Neoral®), rapamycin,FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®, azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3(e.g. Orthocolone®.), AtGam, aspirin, acetaminophen, ibuprofen,naproxen, piroxicam, antiinflammatory steroids (e.g. prednisolone ordexamethasone), methotrexate, statins, anti-TNF agents (e.g., Enbrel®(etanercept) or Humira® (adalimumab)), Orencia® (abatacept),cyclophosphamide, mycophenolic acid, hydroxychloroquine, metformin,mitotic inhibitors, alkylating agents, anti-metabolites, antisense DNAor RNA, intercalating antibiotics, growth factor inhibitors, signaltransduction inhibitors, cell cycle inhibitors, enzyme inhibitors,retinoid receptor modulators, proteasome inhibitors, topoisomeraseinhibitors, biological response modifiers, anti-hormones, angiogenesisinhibitors, cytostatic agents anti-androgens, targeted antibodies,HMG-CoA reductase inhibitors, prenyl-protein transferase inhibitors,radioiodide therapy, external-beam radiation, and radium 223 therapy,wherein the amount of the compound of General Formula I (e.g., any ofthe exemplary compounds described herein), or a pharmaceuticallyacceptable salt or solvate thereof, or pharmaceutical compositionthereof, in combination with the additional therapy or therapeuticagent, is effective in treating said JAK kinase-associated disease ordisorder. In one embodiment, the JAK kinase-associated disease ordisorder is any of the diseases or disorders described hereinabove.

The additional therapeutic agent(s) may be administered as one or moredoses with one or more doses of a compound of General Formula I (e.g.,any of the exemplary compounds described herein), or a pharmaceuticallyacceptable salt or solvate thereof, or pharmaceutical compositionthereof as part of the same or separate dosage forms, by the same ordifferent routes of administration, and on the same or differentadministration schedules according to standard pharmaceutical practiceknown to one skilled in the art.

Also provided herein is (i) a pharmaceutical combination for treating aJAK kinase-associated disease or disorder in a subject in need thereof,which comprises (a) a compound of General Formula I (e.g., any of theexemplary compounds described herein), or a pharmaceutically acceptablesalt or solvate thereof, (b) an additional therapeutic agent, and (c)optionally at least one pharmaceutically acceptable carrier, (e.g., forsimultaneous, separate or sequential use for the treatment of a JAKkinase-associated disease or disorder), wherein the amounts of thecompound of General Formula I, or the pharmaceutically acceptable saltor solvate thereof and of the additional therapeutic agent are togethereffective in treating said JAK kinase-associated disease or disorder;(ii) a pharmaceutical composition including such a combination; (iii)the use of such a combination for the preparation of a medicament forthe treatment of a JAK kinase-associated disease or disorder; and (iv) acommercial package or product including such a combination forsimultaneous, separate or sequential use.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient, e.g. (a) a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof and (b) anothertherapeutic agent, and includes both fixed and non-fixed combinations ofthe active ingredients. The term “fixed combination” means that theactive ingredients, e.g. (a) a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof and (b) anothertherapeutic agent, are both administered to a subject simultaneously inthe form of a single entity or dosage. The term “non-fixed combination”means that the active ingredients, e.g., (a) a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof and(b) another agent, are both administered to a subject as separateentities either simultaneously, concurrently or sequentially with nospecific time limits, wherein such administration providestherapeutically effective levels of the two compounds in the body of thesubject. For a non-fixed combination, the individual active ingredientsof the combination may be administered separately at different timesduring the course of therapy or concurrently in divided or singlecombination forms.

As used herein, the terms “treat” or “treatment” or “treating” mean analleviation, in whole or in part, of symptoms associated with a diseaseor disorder or condition (e.g., a JAK kinase-associated disease ordisorder, such as any of the diseases and disorders described herein,including autoimmune diseases, inflammatory diseases, rejection oftransplanted organs, tissues and cells, and hematologic disorders andmalignancies and their co-morbidities), or slowing, or halting offurther progression or worsening of those symptoms.

As used herein, the term “prevent” or “preventing” as used herein meansthe prevention of the onset, recurrence or spread, in whole or in part,of the disease or disorder or condition (e.g., a JAK kinase-associateddisease or disorder, such as any of the diseases and disorders describedherein, including autoimmune diseases, inflammatory diseases, rejectionof transplanted organs, tissues and cells, and hematologic disorders andmalignancies and their co-morbidities), or a symptom thereof.

The terms “effective amount” and “therapeutically effective amount”refer to an amount of compound that, when administered to a subject inneed of such treatment, is sufficient to (i) treat a particular disease,condition, or disorder, (ii) attenuate, ameliorate, or eliminate one ormore symptoms of the particular disease, condition, or disorder, (iii)delay the onset of one or more symptoms of the particular disease,condition, or disorder, or (iv) prevention of the onset, recurrence orspread, in whole or in part, of the disease or condition describedherein. The amount of a compound of General Formula I that willcorrespond to such an amount will vary depending upon factors such asthe particular compound, the disease condition and its severity, and theidentity (e.g., weight) of the subject in need of treatment, but cannevertheless be routinely determined by one skilled in the art.

As used herein, the term “subject,” “individual,” or “patient,” usedinterchangeably, refers to refers to any animal, including mammals. Insome embodiments, the subject is a human. In some embodiments, thepatient is a human. In some embodiments, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented. In some embodiments, the subject has beenidentified or diagnosed as having a JAK kinase-associated disease ordisorder. In some embodiments, the subject is a pediatric patient (i.e.a patient under the age of 21 years at the time of diagnosis ortreatment). The term “pediatric” can be further divided into varioussubpopulations including: neonates (from birth through the first 28 daysof life); infants (29 days of age to less than two years of age);children (two years of age to less than 12 years of age); andadolescents (12 years of age through 21 years of age (up to, but notincluding, the twenty-second birthday)).

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, primates (including humans), guinea pigs, dogs,cats, rats, mice and hamsters. In some embodiments, the mammal is ahuman.

Compounds of General Formula I or pharmaceutically acceptable salts orsolvates thereof may be administered by any convenient route, e.g. intothe gastrointestinal tract (e.g. rectally or orally), the nose, lungs,musculature or vasculature, or topical (e.g., transdermal, dermal,ophthalmic, and to the mucous membranes including intranasal, vaginaland rectal delivery). Compounds of General Formula I or pharmaceuticallyacceptable salts or solvates thereof may be administered in anyconvenient administrative form, e.g. tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, ointments, creams, etc. Such compositions maycontain components conventional in pharmaceutical preparations, e.g.diluents, carriers, pH modifiers, sweeteners, bulking agents, andfurther active agents. If parenteral administration is desired, thecompositions will be sterile and in a solution or suspension formsuitable for injection or infusion. Such compositions form a furtheraspect of the invention.

A typical formulation is prepared by mixing a compound described hereinand a carrier or excipient. Suitable carriers and excipients are wellknown to those skilled in the art.

The compositions comprising as the active ingredient a compound ofGeneral Formula I as provided herein or a pharmaceutically acceptablesalt or solvate thereof can be formulated in a unit dosage form, eachdosage containing from about 5 to about 1,000 mg (1 g), more usuallyabout 100 mg to about 500 mg, of the active ingredient. The term “unitdosage form” refers to physically discrete units suitable as unitarydosages for administration to the subject in need thereof, each unitcontaining a predetermined quantity of the active ingredient calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient.

In some embodiments, the compositions provided herein contain from about5 mg to about 50 mg of the active ingredient. One having ordinary skillin the art will appreciate that this embodies compounds or compositionscontaining about 5 mg to about 10 mg, about 10 mg to about 15 mg, about15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40mg to about 45 mg, or about 45 mg to about 50 mg of the activeingredient.

In some embodiments, the compositions provided herein contain from about50 mg to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 50 mg to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about450 mg to about 500 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about500 mg to about 1,000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 500 mg to about 550 mg, about 550 mg toabout 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg toabout 950 mg, or about 950 mg to about 1,000 mg of the activeingredient.

The active ingredient may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

Accordingly, provided here in is a pharmaceutical composition, whichcomprises a compound of General Formula I (e.g., any of the exemplarycompounds described herein) or a pharmaceutically acceptable salt orsolvate thereof, as defined hereinabove, and a pharmaceuticallyacceptable carrier. In one embodiment, the pharmaceutical composition isformulated for oral administration. In one embodiment, thepharmaceutical composition is formulated as a tablet or capsule.

Also provided herein is a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof, for use in therapy. In one embodiment, providedherein is a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of cytokineor JAK kinase-associated diseases in a subject.

In one embodiment, provided herein is a compound of General Formula I ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, for use in the treatment ofautoimmune diseases and inflammatory diseases in a subject.

In one embodiment, provided herein is a compound of General Formula I ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, for use in the prevention ofautoimmune diseases and inflammatory diseases in a subject.

In one embodiment, provided herein is a compound of General Formula I ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, for use in the treatment oftransplant rejection in a subject.

In one embodiment, provided herein is a compound of General Formula I ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, for use in the prevention oftransplant rejection in a subject.

In one embodiment, provided herein is a compound of General Formula I ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, for use in the treatment ofhematologic disorders and malignancies in a subject.

According to a further aspect, provided herein is the use of a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof, in the treatment ofcytokine or JAK kinase-associated diseases in a subject.

In one embodiment, provided herein is the use of a compound of Formula Ior a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, in the treatment of autoimmunediseases and inflammatory diseases.

In one embodiment, the invention provides the use of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition thereof, in the treatment oforgan, tissue or cell transplant rejection in a subject.

In one embodiment, provided herein is the use of a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof, in the treatment of malignancies ina subject.

Also provided herein is method for inhibiting JAK kinase activity in acell, the method comprising contacting the cell with a compound ofFormula I or pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof. In one embodiment, the cell is amammalian cell. In one embodiment, the contacting occurs in vitro. Inone embodiment, the contacting occurs in vivo.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a JAK kinase with a compound provided hereinincludes the administration of a compound provided herein to anindividual or patient, such as a human, having a JAK kinase, as well as,for example, introducing a compound provided herein into a samplecontaining a cellular or purified preparation containing the JAK kinase.

Provided herein are pharmaceutical kits useful, for example, in thetreatment of JAK kinase-associated diseases or disorders, which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof,provided herein. Such kits can further include, if desired, one or moreof various conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

One skilled in the art will recognize that both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof, to treat or prevent a given disease or disorder.

One skilled in the art will further recognize that human clinical trialswith a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof, or a pharmaceutical composition thereof,including first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers and were used without further purification unless otherwiseindicated.

General Enzyme Inhibition Assay Method

The assays described in Examples A, B, C and D for the determination ofTyk2, JAK1, JAK2 and JAK3 kinase activity, respectively, utilized theOmnia® Kinase fluorescence peptide substrate-based technology(Invitrogen). The specific components of the assay mixture are describedin Examples A, B, C and D. In these assays, Mg²⁺ is chelated uponphosphorylation of the Omnia peptide by the kinase to form a bridgebetween the chelation-enhanced fluorophore Sox and the phosphate,resulting in an increase in fluorescence emission at 485 nM when excitedat 360 nM. The reactions were therefore read at excitation 360 nm andemission was measured at 485 nm every 50 seconds for 45 minutes using aPerkinElmer EnVision Multilabel Plate Reader.

The final buffer conditions for Tyk2, JAK1, JAK2, and JAK3 assays wereas follows: 25 mM HEPES, pH 7.4, 10 mM MgCl₂, 0.01% Triton X-100 and 1mM DTT.

IC₅₀ Determinations

Compounds were prepared at 50× the final concentration in DMSO byconducting 3-fold serial dilutions from a 500-μM intermediate dilutionto give a 10-point dosing curve having a high dose of 10 μM. Two-μLaliquots of these were transferred to a fresh plate for a ten-foldintermediate dilution with assay buffer. Five-μL aliquots of the dilutedcompounds were then transferred to 20-μL of assay mixtures described inExamples A, B, C and D for a final concentration of DMSO of 2%. Astandard or reference compound was typically included on each assayplate to validate that plate. For each plate, percent of control (POC)values were calculated for each well according to the followingequation:

${{POC} = {\frac{{Sample} - {\overset{\_}{X}}_{m\; i\; n}}{{\overset{\_}{X}}_{m\; {ax}} - {\overset{\_}{X}}_{m\; i\; n}} \times 100}},$

where

X _(max)=Average Uninhibited Controls

X _(min)=Average Background

IC₅₀'s were estimated from the POC's using a standard 4-parameterlogistic model:

${Y = {A + \frac{B - A}{1 + \left( \frac{C}{X} \right)^{D}}}},$

where

-   -   A=Minimum Y (Bottom Asymptote)    -   B=Maximum Y (Top Asymptote)    -   C=EC₅₀    -   D=Slope Factor    -   X=Compound Concentration (nM)    -   Y=POC

The IC₅₀ is defined as the concentration of inhibitor at which the POCequals 50 for the fitted curve.

Example A Tyk2 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit Tyk2using the general enzyme inhibition assay method, in which the assaymixture contained 1 mM ATP, 8 μM Omnia Y12 peptide (Catalog # IVGNKPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 1 nM Tyk2 in atotal volume of 25 μL. Human Tyk2 kinase domain, comprising amino acids886 to 1187 with 10 additional histidine residues (histidine tag) on thecarboxy terminus, was expressed and purified from bacculovirus in-houseat Array BioPharma Inc. (Boulder, Colo.). The histidine tag was cleavedafter purification using standard conditions.

Example B JAK1 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit JAK1using the general enzyme inhibition assay method, in which the assaymixture contained 1 mM ATP, 8 μM Omnia® Y12 peptide (Catalog # IVGNKPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 12.5 nM JAK1 ina total volume of 25 μL. JAK1 was purchased from Invitrogen Corporation,Carlsbad, Calif. (catalog # IVGN PV4775).

Example C JAK2 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit JAK2using the general enzyme inhibition assay method, in which the assaymixture contained 1 mM ATP, 10 μM Omnia® Y7 peptide (Catalog # IVGNKNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 4 nM JAK2 in atotal volume of 25 μL. JAK2 was purchased from Invitrogen Corporation,Carlsbad, Calif. (catalog # IVGN PV4288).

Example D JAK3 Inhibition Assay

Compounds of Formula I were screened for their ability to inhibit JAK3using the general enzyme inhibition assay method, in which the assaymixture contained 1 mM ATP, 10 μM Omnia® Y7 peptide (Catalog # IVGNKNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 2 nM JAK3 in atotal volume of 25 μL. JAK3 was purchased from Invitrogen Corporation,Carlsbad, Calif. (catalog # IVGN PV4080).

Table 1 provides averaged IC₅₀ ranges for compounds described in theExamples when tested in the assays described in Examples A, B, C and D.For each IC₅₀ value shown in Table 1, “A” represents an IC₅₀ value ofless than 10 nM, “B” represents an IC₅₀ value of greater than 10 nM andless than 100 nM, “C” represents an IC₅₀ value of greater than 100 nMand less than 1000 nM, and “D” represents an IC₅₀ value of greater than1000 nM and less than or equal to 10,000 nM.

TABLE 1 TYK2 JAK1 JAK2 JAK3 Ex. Enzyme IC₅₀ Enzyme IC₅₀ Enzyme IC₅₀Enzyme IC₅₀ # 1 mM ATP 1 mM ATP 1 mM ATP 1 mM ATP 1 D D D D 2 C D C D 3B D B D 4 B C B D 5 B C C D 6 B B B D 7 B D B D 8 B B B D 9 B C B D 10 BD B D 11 B D B D 12 C D C D 13 B C A D 14 B B B D 15 B B B D 16 B B B D17 B C B D 18 B B B D 19 D D D D 20 B B B D 21 C D B D 22 B C B D 23 B CB D 24 B C B D 25 B C B D 26 C D C D 27 B D B D 28 B D B D 29 B C B D 30B C B D 31 B C A D 32 A B A D 33 A C A D 34 B B A D 35 B C B D 36 A C AD 37 B C A D 38 B C B D 39 B B B D 40 B C B D 41 B C B D 42 B D B D 43 BD B D 44 B D D D 45 D D D D 46 N/T N/T N/T N/T 47 D D D D 48 A B A D 49C D D D 50 D D C C 51 C D D D 52 B C B D 53 C D C D 54 B C B D 55 B C CD 56 B D B D 57 B C B D 58 B C B D 59 B C B D 60 B D B D 61 B C B D 62 BC B D 63 B C B D 64 B C B D 65 B C B D 66 B B B C 67 C C B C 68 B C B D69 C D C D 70 B C B D 71 C D C D 72 C C C D 73 B D B D 74 B D C D 75 C DC D 76 C D C D 77 C D C D 78 C D C D 79 B B B D 80 C D C D 81 B C B D 82C C B D 83 B D B D 84 B B B D 85 C D A D 86 A C B D 87 C D C D 88 C D CD 89 B C B D Peak A 90 B C B D Peak B 91 B C B D Peak A 92 B C B D PeakB 93 B D C D Peak A 94 B C B D Peak B 95 D D D N/T Peak A 96 D D C DPeak B 97 B C C D 98 B D B D 99 B D B D 100 B D B D 101 B D B D 102 C DB D 103 B D B D 104 B D B D 105 C D C D 106 C D C D 107 B C B D 108 B CB D 109 C D D D 110 B C B D 111 B C B D 112 C D C D 113 B D C D 114 B CB D 115 B C B D 116 B D B D 117 C C C D 118 B B A D 119 A C B D 120 B CB D 121 B C B D 122 B B B D 123 B C B D 124 B C B D 125 B D C D 126 B CB D 127 C D C D 128 C D C D 129 B C B D 130 B D B D 131 B C B D 132 B CB D Peak A 133 B B A D Peak B 134 B B B D 135 B D B D 136 B C B D 137 BC B D 138 B D B D 139 B C C D 140 B D B D 141 B D B D 142 B D B D 143 CD B D 144 B C B D 145 C C B D 146 B D B D 147 B D B D 148 C D C D Peak A149 B D B D Peak B 150 B D B D Peak A 151 B C B D Peak B 152 B D B DPeak B 153 B C B D Peak A 154 B C B D Peak B 155 B C B D Peak A 156 B CB D Peak B 157 B C B D Peak A 158 B B B D Peak B 159 B C B D Peak A 160B D B D Peak B 161 B C B D 162 A C B D 163 B C A D Peak A 164 C D C DPeak B 165 B C B D 166 B C B D 167 B C B D 168 B D B D 169 C D C D 170 BC B D 171 B C B D 172 B B B D 173 B C B D 174  B. C B D 175 C D B D 176A C C D 177 A C B D 178 B D B D 179 B D B D 180 C D C D 181 B C B D 182B C B D 183 B D B D 184 C D C D 185 C C C D 186 B D B D 187 B C B D 188B D B D 189 B D B D Peak A 190 C D C D Peak B 191 B B B D 192 B B B D193 C D C D 194 C D C D Peak A 195 C D C D Peak B 196 C D C D Peak A 197B C B D Peak B 198 C D C D Peak A 199 C D C D Peak B 200 B C B D Peak A201 B D B D Peak B 202 B C B D Peak A 203 B C B D Peak B 204 C D C DPeak A 205 B C B D Peak A 206 C D C D Peak B 207 B C A C Peak A 208 C DB D Peak B 209 B C B D Peak A 210 C D C D Peak B 211 B C B D Peak A 212C D C D Peak B 213 B C B D Peak B 214 B C C D Peak A 215 B C B D Peak B216 C D C D 217 C D C D 218 B C B D N/T = Not tested in the assaysdescribed in Examples A, B, C and D but found to be active when testedin alternative Tyk2, JAK1, JAK2 and JAK3 enzyme assay protocols.

Preparation of Synthetic Intermediates Preparation 14-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride

Step A: In 250 mL of acetonitrile was dissolved2-chloro-1-(1-methyl-1H-pyrazol-4-yl)ethanone (18.3 g, 115 mmol) anddiethyl 1H-pyrazole-3,5-dicarboxylate (24.5 g, 115 mmol) before finelyground K₂CO₃ (31.9 g, 231 mmol) was added in one portion. The reactionmixture was stirred at ambient temperature overnight. The reactionmixture was filtered and the cake was washed with acetonitrile (100 mL).The filtrate was concentrated in vacuo to a thick oil. The oil wasdissolved in EtOAc (80 mL), and heptane (200 mL) was added slowly withstirring. The resultant solids were stirred for 2 hours, then filteredand washed with heptane. The solids were dried in a vacuum oven toafford diethyl1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate(26.4 g, 77.4 mmol, 67.1% yield).

Step B: In 320 mL of acetic acid were combined diethyl1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate(8.0 g, 23.9 mmol) and NH₄OAc (55.3 g, 718 mmol) in a 500 mL glasspressure vessel. The vessel was sealed and the reaction mixture washeated to 120° C. overnight, followed by heating at 160° C. for 48hours. The reaction mixture was cooled to ambient temperature and thenpoured into a 2 L flask. Water (960 mL) was slowly added and the mixturewas stirred with cooling for 2 hours. The fine pink suspension thatresulted after stirring overnight was collected by vacuum filtration Thesolids were collected and dried in a vacuum oven to afford a 2:1 mixtureof ethyl4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate(5.45 g, 6.26 mmol, 26.2% yield) and4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicacid (5.45 g, 13.9 mmol, 58.0% yield).

Step C: Crude ethyl4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate(10.00 g, 34.81 mmol) was charged to a 500 mL flask equipped withmechanical stirring, a thermocouple, and a reflux condenser equippedwith a nitrogen balloon. 6 N HCl (100 mL) was added and the reactionmixture was heated to 65° C. for 32 hours. The reaction mixture wascooled to ambient temperature overnight and water (100 mL) was added.The reaction mixture was stirred for 1 hour and then filtered. Theresulting solids were rinsed with water and dried in the vacuum ovenovernight to afford6-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylicacid (8.8 g, 33.95 mmol, 97.5% yield).

Step D:6-(1-Methyl-1H-pyrazol-4-yl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylicacid (10.0 g, 38.6 mmol) was added to a 500 mL flask equipped withmechanical stirring, a thermocouple, a reflux condenser and staticnitrogen pressure. Cu(OAc)₂ (3.5 g, 19.3 mmol), 1,10-phenanthroline (3.5g, 19.3 mmol) and N-methylpyrrolidone (100 mL) were added. The reactionmixture was heated to 165° C. overnight. The reaction mixture was cooledto ambient temperature, and 3 M HCl (200 mL) was added to afford aslurry, which was stirred overnight. The product was collected by vacuumfiltration, rinsed with water, and dried in the vacuum oven overnight toafford 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4(5H)-one (8.0g, 37.2 mmol, 96.4% yield).

Step E: To a 100 mL 3-neck flask fitted with a magnetic stir bar,internal temperature probe, and reflux condenser was added6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4(5H)-one (5.0 g,23.2 mmol), followed by phosphoryl trichloride (34.6 mL, 371 mmol). Thereaction mixture was heated to 80° C. under nitrogen for 7 hours. Thereaction mixture was cooled to 50° C., then charged with 40 mL ofacetonitrile and cooled to ambient temperature. The resulting solidswere filtered, washed with 20 mL of acetonitrile and dried in a vacuumoven to afford 2.65 g of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride. The filtrates were diluted with 80 mL of methyltert-butyl ether and the reaction mixture was stirred at ambienttemperature overnight. The resultant solids were filtered and dried toafford an additional 2.97 g of product. The total yield of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride was 4.55 g (16.8 mmol, 72.5% yield).

Preparation 24-chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride

Step A: 4-Iodo-1H-pyrazole (5.0 g, 25.8 mmol) was dissolved in DMF (50mL), and K₂CO₃ (4.27 g, 30.9 mmol) was added followed by1-(chloromethyl)-4-methoxybenzene (3.86 mL, 28.4 mmol). The reactionmixture was stirred at ambient temperature overnight. The reactionmixture was then poured into water and extracted with Et₂O, washed withbrine, dried over sodium sulfate, filtered and concentrated to afford4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (8.3 g, 26.4 mmol, 103% yield).

Step B: 4-Iodo-1-(4-methoxybenzyl)-1H-pyrazole (8.1 g, 26 mmol) wasdissolved in THF (50 mL) and cooled in an ice bath. Isopropylmagnesiumchloride (2.9 M, 8.9 mL, 26 mmol) was added slowly. The reaction mixturewas stirred for 10 minutes, and then2-chloro-N-methoxy-N-methylacetamide (3.5 g, 26 mmol) dissolved in THF(15 mL) was added slowly by syringe. The reaction mixture was warmed toambient temperature and stirred for 1 hour. The reaction mixture waspartitioned between EtOAc and 1N HCl, and the organic layer was driedover sodium sulfate, filtered and concentrated to afford crude2-chloro-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethanone (7.1 g, 27mmol, 104% yield) as an amber oil that slowly solidified.

Step C: Crude 2-chloro-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethanone(7.1 g, 21 mmol) was dissolved in acetonitrile (100 mL). Diethyl1H-pyrazole-3,5-dicarboxylate (4.6 g, 21 mmol) was added, followed byK₂CO₃ (5.9 g, 43 mmol), and the reaction mixture was stirred at 45° C.for 1 hour. The reaction mixture was cooled to ambient temperature,diluted with EtOAc, filtered and concentrated. The residue was purifiedover silica gel to afford diethyl1-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate(8.7 g, 20 mmol, 92% yield) as a white solid.

Step D: Diethyl1-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate(8.2 g, 18.6 mmol) was dissolved in HOAc (100 mL) and NH₄OAc (43.1 g,559 mmol) was added. The reaction mixture heated in a sealed tube at120° C. for 48 hours. The reaction mixture was cooled to ambienttemperature, poured into water (200 mL), filtered and dried to affordethyl4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate(5.65 g, 14.4 mmol, 77.1% yield) as a white solid.

Step E: Ethyl4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate(5.4 g, 14 mmol) was suspended in THF (60 mL), and 1M lithium hydroxide(30 mL, 30 mmol) was added. The reaction mixture was heated to 50° C.for 30 minutes. The reaction mixture was quenched with slow addition of1M HCl (35 mL) with vigorous stirring. Additional water (10 mL) wasadded to aid in stirring. The mixture was stirred vigorously at 50° C.for 15 minutes, then cooled and filtered. The isolated solids werewashed with water and dried in vacuum oven to afford4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicacid (4.6 g, 13 mmol, 92% yield) as a white solid.

Step F:4-Hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicacid (4.6 g, 13 mmol) was charged to a 25 mL flask and1,10-phenanthroline (1.00 g, 5.5 mmol) and diacetoxycopper (1.0 g, 5.5mmol) were added. The reaction mixture was diluted withN-methylpyrrolidone (12 mL) and then heated to 165° C. under nitrogenfor 6 hours. The reaction mixture was cooled to ambient temperatureovernight, transferred to a flask with 1N HCl (20 mL) and stirred at 50°C. for 45 minutes. The reaction mixture was then filtered, and theisolated solids were washed with water and dried in vacuum oven toafford 4.7 g of a dark brown solid. The dried solid was suspended in 1NHCl (60 mL), and N-methylpyrrolidone (10 mL) was added to aid inwetting. The mixture was stirred at 65° C. for 1 hour. The mixture wasfiltered and the isolated solids were washed with water until theresulting filtrate was colorless. The isolated solids were dried invacuum oven to afford6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (3.7g, 12 mmol, 91% yield) as a brown solid.

Step G:6-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (3.7g, 11.5 mmol) was suspended in phosphoryl trichloride (10.6 mL, 115mmol) and heated to 80° C. under nitrogen for 3 hours. The reactionmixture was cooled to ambient temperature and poured into methyltert-butyl ether (80 mL) with vigorous stirring. The mixture was stirredfor 10 minutes and then filtered. The isolated solids were washed withmethyl tert-butyl ether and dried in vacuum oven to afford 2.7 g of thedesired product as a tan solid. After sitting for 2 days, the filtratehad solids as well. These were filtered and dried to afford anadditional 1.2 g of4-chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (Total yield: 3.9 g, 10.4 mmol, 90.0% yield).

Preparation 3 4-chloro-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

To a 150 mL glass bomb were added4-chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(10.0 g, 29.4 mmol), anisole (16.0 mL, 147 mmol), 2,2,2-trifluoroaceticacid (45.3 mL, 589 mmol), and trifluoromethanesulfonic acid (5.26 mL,58.9 mmol) were combined and then sealed and heated to 75° C. for 4hours. The reaction mixture was diluted with CH₃CN and concentratedunder reduced pressure. The resulting warm oil was immediately quenchedwith saturated sodium bicarbonate and extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue taken up in 100 mL of CH₂Cl₂ and sonicatedfor 2 hour, stirred for 1 hour, and sonicated and then stirredintermittently over the next 30 min to create a fine suspension. Thesolid was collected by vacuum filtration and dried to afford4-chloro-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (6.99 g, 28.6 mmol,97.3% yield).

Preparation 41-(pentan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.0 g,20.61 mmol), 3-bromopentane (5.121 mL, 41.23 mmol) and Cs₂CO₃ (8.060 g,24.74 mmol) were suspended in DMF (8 mL) and sealed in a glass pressurevessel and heated to 100° C. overnight. After cooling to ambienttemperature, the cap was removed slowly [pressure release], partitionedbetween water (20 mL) and EtOAc (100 mL), washed with water and brine,dried over sodium sulfate, filtered and concentrated. The residue waspurified over silica gel (15% EtOAc in hexanes) to afford1-(pentan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.8 g, 14.38 mmol, 69.78% yield) as a clear colorless oil.

Preparation 5(S)-1-(4-methylpentan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step A: A solution of (R)-4-methylpentan-2-ol (3.74 mL, 29.4 mmol) inanhydrous CH₂Cl₂ (30 mL) at 0° C. was treated with diisopropylethylamine(10.3 mL, 7.59 mmol) followed by the dropwise addition of mesyl chloride(2.5 mL, 32.3 mmol). The mixture was stirred for 2 hours and partitionedbetween saturated aqueous NaHCO₃ (50 mL) and CH₂Cl₂ (50 mL) and theaqueous layer was extracted with CH₂Cl₂ (2×30 mL). The combined organicphases were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to afford (R)-4-methylpentan-2-yl methanesulfonate as abrown oil that was used directly in the next reaction withoutpurification.

Step B: To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.59 g,18.5 mmol) in anhydrous DMA (10 mL) was added (R)-4-methylpentan-2-ylmethanesulfonate (5.0 g, 27.7 mmol) followed by cesium carbonate (12.0g, 37.0 mmol). The mixture was stirred in a sealed vessel at 80° C.overnight. The mixture was partitioned between water (100 mL) and EtOAc(50 mL) and the aqueous layer extracted with EtOAc (2×50 mL). Thecombined organic phases were washed with water (5×30 mL) and brine (30mL) then dried over Na₂SO₄, filtered and concentrated to afford a brownoil. The oil was purified over silica gel (9:1 hexane:EtOAc) to afford(S)-1-(4-methylpentan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.21 g, 62.4% yield) as a pale yellow oil.

The following compounds were synthesized using the procedure describedin Preparation 3 or 4.

Preparation Structure Name  6

1-(sec-butyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole  7

(R)-1-(sec-butyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole  8

(S)-1-(sec-butyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole  9

1-(pentan-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 10

(R)-1-(pentan-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 11

(S)-1-(pentan-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 12

4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazole 13

(R)-1-(4-methylpentan-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14

1-(1-phenylpropyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 15

(R)-1-(1-phenylpropyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 16

(S)-1-(3-methylbutan-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 17

1-(2-methylpentan-3-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 18

4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)-1H-pyrazole 19

1-(tetrahydrofuran-3-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 20

1-cyclohexyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 21

1-(cis-2-methylcyclohexyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 22

1-(cis-2-methylcyclopentyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 23

1-(1-cyclobutylpropyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 24

1-cycloheptyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 25

1-(2-methylcycloheptyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 26

methyl 2-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanoate 27

tert-butyl 2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanoate 28

1-(1-methoxybutan-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 29

1-(1-methoxypropan-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 30

3-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl)pentan-2-one 31

1-(1-cyclopentylpropyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 32

(R)-1-(1-methoxypropan-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 33

(S)-1-(1-methoxypropan-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 34

methyl 2-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)cyclopentanecarboxylate 35

(S)-tert-butyl 3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine- 1-carboxylate 36

(R)-tert-butyl 3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine- 1-carboxylate

Preparation 371-(trans-2-methylcyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step A: 2-Methylcyclohexanone (5.41 mL, 44.6 mmol) and tert-butylhydrazinecarboxylate (6.19 g, 46.8 mmol) were dissolved in EtOH (50 mL)and stirred at ambient temperature overnight. The reaction mixture wasconcentrated and suspended in 1:1 water:acetic acid (30 mL). NaCNBH₃(2.94 g, 46.8 mmol) was added in portions and the reaction mixture wasstirred at room temperature for 3 hours. The mixture was slowly pouredinto EtOAc (120 mL) and 2M K₂CO₃ (40 mL). The organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified over silica gel (10% EtOAc inhexanes) to afford tert-butyl2-(cis-2-methylcyclohexyl)hydrazinecarboxylate (3.0 g) (having thehigher R_(f)), and tert-butyl2-(trans-2-methylcyclohexyl)hydrazinecarboxylate (4.1 g, 18.0 mmol,40.3% yield) (having the lower R_(f)).

Step B: tert-Butyl 2-(trans-2-methylcyclohexyl)hydrazinecarboxylate (4.1g, 18.0 mmol) was dissolved in EtOH (25 mL). Hydrogen chloride (10 M,3.59 mL, 35.9 mmol) was added and the reaction mixture was heated to 75°C. for 10 minutes. 1,1,3,3-Tetramethoxypropane (2.96 mL, 18.0 mmol) wasadded and the reaction mixture was heated for 2 hours. The reactionmixture was cooled to room temperature, concentrated, partitionedbetween EtOAc and saturated aqueous NaHCO₃, dried over sodium sulfate,filtered and concentrated. The residue was purified over silica gel (20%EtOAc in hexanes) to afford 1-(trans-2-methylcyclohexyl)-1H-pyrazole(1.5 g, 9.13 mmol, 50.9% yield).

Step C: 1-(Trans-2-methylcyclohexyl)-1H-pyrazole (1.5 g, 9.1 mmol) wasdissolved in CH₂Cl₂ (30 mL) and 1-bromopyrrolidine-2,5-dione (2.0 g, 11mmol) was added. The reaction mixture was stirred at room temperaturefor 3.5 hours. The reaction mixture was partitioned between CH₂Cl₂ andwater, washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified over silica gel (10% EtOAc inhexanes) to afford 4-bromo-1-(trans-2-methylcyclohexyl)-1H-pyrazole (2.0g, 8.2 mmol, 90% yield) as a clear colorless oil.

Step D: 4-Bromo-1-(trans-2-methylcyclohexyl)-1H-pyrazole (2.0 g, 8.23mmol) was dissolved in dioxane (80 mL) and treated with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.30 g,9.05 mmol) and potassium acetate (2.42 g, 24.7 mmol). Argon was bubbledthrough the reaction mixture for 1 minute. PdCl₂(dppf)*CH₂Cl₂ (0.672 g,0.823 mmol) was added and Argon was bubbled through the reaction mixturefor 1 minute. The reaction mixture was sealed and heated to 95° C.overnight. The reaction mixture was diluted with EtOAc, filtered throughCelite® and concentrated. The residue was purified over silica gel (5 to10% EtOAc in hex) to afford1-(trans-2-methylcyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.35 g, 4.65 mmol, 56.6% yield) as a white solid.

The following compounds were synthesized according to the proceduredescribed in Preparation 37.

Preparation Structure Name 38

1-(2,2-dimethylcyclopentyl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole 39

1-(cis-2-methylcyclobutyl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole 40

1-(trans-2- methylcyclobutyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole 41

4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-(1,1,1-trifluoropentan-3-yl)-1H- pyrazole

Preparation 421-(1-cyclopropylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step A: Ethylmagnesium chloride (8.20 mL, 16.4 mmol) was added to 50 mLof THF, followed by cooling to 0° C. Cyclopropanecarbaldehyde (1.00 g,14.3 mmol) in 10 mL of THF was added dropwise to the Grignard solutionover 10 minutes. The reaction mixture was stirred at 0° C. for 1 hour,then quenched with NH₄Cl. The reaction mixture was back extracted withEt₂O, dried over Magnesium sulfate, and concentrated in vacuo (19° C.bath temp), affording the desired adduct 1-cyclopropylpropan-1-ol (0.998g, 9.96 mmol, 69.8% yield) as a light tan oil.

Step B: A round bottom flask equipped with a stir bar and nitrogen inletwas charged with 4-iodo-1H-pyrazole (0.50 g, 2.58 mmol) and 25 mL of dryCH₂Cl₂. To this was added 1-cyclopropylpropan-1-ol (0.31 g, 3.09 mmol)and resin-bound triphenylphosphine (1.36 g, 3.09 mmol, 2.27 mmol/g). Themixture was stirred at room temperature for 10 minutes and then chilledto 0° C. Diisopropyl azodicarboxylate (0.607 mL, 3.09 mmol) was added bysyringe and the mixture was allowed to stir at 0° C. for 10 minutes,then allowed to warm to room temperature for 3 hours. The reactionmixture was filtered and the filtrate concentrated under reducedpressure. The resulting material was passed through a 40 g Redi Sepcolumn, eluting with 15% ethyl acetate:Hexane to afford1-(1-cyclopropylpropyl)-4-iodo-1H-pyrazole (0.140 g, 0.507 mmol) as anoil.

Step C: A round bottom flask equipped with a stir bar and nitrogen inletwas charged with 1-(1-cyclopropylpropyl)-4-iodo-1H-pyrazole (0.140 g,0.507 mmol), dry THF (5 mL), and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.283 g, 1.52mmol). The reaction mixture was chilled to 0° C. and isopropylmagnesiumlithium chloride (1.06 mL, 1.01 mmol, 0.96 M) was added by syringe. Themixture was stirred for 1 hour, quenched with saturated ammoniumchloride solution and allowed to warm to room temperature. Water wasadded and the mixture was extracted with EtOAc. The combined organicextracts were dried over sodium sulfate and concentrated under reducedpressure to afford1-(1-cyclopropylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.120 mg, 85.7% yield) as an oil.

The following compounds were synthesized according to the proceduredescribed for Preparation 42.

Preparation Structure Name 43

1-(1-(3,3-difluorocyclobutyl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole 44

1-(dicyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole

Preparation 451-(1-cyclopropylbutan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step A: A round bottom flask equipped with a stir bar and nitrogen inletwas charged with 2-cyclopropylacetic acid (3.00 g, 30.0 mmol) and 120 mLof dry CH₂Cl₂. The reaction mixture was chilled to 0° C. and to this wasadded N,O-dimethylhydroxylamine hydrochloride (3.51 g, 36.0 mmol), EDCI(6.89 g, 36.0 mmol), HOBt (4.86 g, 36.0 mmol), and diisopropylethylamine(3.87 g, 36.0 mmol). The reaction mixture was allowed to warm to roomtemperature overnight, then diluted with CH₂Cl₂, washed with 10% aqueousK₂CO₂, dried over sodium sulfate and concentrated under reduced pressureto give 3.77 g of 2-cyclopropyl-N-methoxy-N-methylacetamide as an oil.

Step B: A round bottom flask containing2-cyclopropyl-N-methoxy-N-methylacetamide (3.7 g, 26 mmol) and 130 mL ofEt₂O was chilled to −78° C. To this was added ethylmagnesium bromide (78mL, 78 mmol, 1M in THF) and the reaction mixture was stirred at −78° C.for 20 minutes, then allowed to warm to room temperature and quenched bythe slow addition of 1M aq. HCl. The mixture was diluted with water andextracted with EtOAc. The combined organic extracts were dried oversodium sulfate and concentrated under reduced pressure to give 1 g of1-cyclopropylbutan-2-one as an oil.

Step C: A round bottom flask containing 1-cyclopropylbutan-2-one (1.0 g,8.92 mmol) was charged with 90 mL of methanol and chilled to 0° C. Tothis was added sodium borohydride (0.675 g, 17.8 mmol) and the mixturewas stirred at 0° C. for 10 minutes, then allowed to warm to roomtemperature. The mixture was concentrated under reduced pressure andquenched with saturated ammonium chloride solution. Water was added andthe mixture was extracted with EtOAc, dried over sodium sulfate andconcentrated under reduced pressure to give 543 mg of-cyclopropylbutan-2-ol as an oil.

Steps D and E: Following the procedures described in Preparation 42,Steps B and C, 1-cyclopropylbutan-2-ol was converted to1-(1-cyclopropylbutan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

The following compound was synthesized following the procedure describedin Preparation 45.

Preparation Structure Name 46

1-(1-(2,2- difluorocyclopropyl) propyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole

Preparation 471-(1-ethoxethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step A: 4-Iodo-1H-pyrazole (5.0 g, 25.8 mmol) was suspended in toluene(50 mL) and ethoxyethene (3.70 mL, 38.7 mmol) was added. To thesuspension was added HCl [4M in dioxane] (0.161 mL, 0.644 mmol) and thereaction mixture was heated to 35° C. for 1 hour. The reaction mixturewas quenched with solid NaHCO₃ and stirred for 1 hour. The reactionmixture was filtered and concentrated. The residue was purified byKugelrohr distillation to afford 1-(1-ethoxyethyl)-4-iodo-1H-pyrazole(7.1 g, 26.7 mmol, 104% yield) as a pale yellow oil.

Step B: In 15 mL of DMSO were combined1-(1-ethoxyethyl)-4-iodo-1H-pyrazole (4.0 g, 15 mmol),bis(pinacolato)diboron (5.7 g, 23 mmol), KOAc (4.4 g, 45 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (0.61 g, 0.75 mmol). The reaction mixture wasstirred and sparged with argon for 10 minutes, and the flask was thensealed and the reaction mixture was heated to 70° C. overnight. To thereaction mixture was added 200 mL of 1:1 saturated sodiumbicarbonate:water and the mixture was extracted with EtOAc. The combinedorganic layers were washed with 150 mL of brine. The combined aqueouswashes were back extracted with EtOAc (300 mL). The combined organiclayers were dried over MgSO₄, filtered and concentrated. The residue waspurified over silica gel (20% EtOAc in hexanes) to afford1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.9 g, 11 mmol, 72% yield).

Preparation 48 methyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pentanoate

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4 g, 21mmol) in CH₃CN (30 mL) was added2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.31 g, 2.1 mmol) and(E)-methyl pent-2-enoate (3.3 g, 29 mmol) and the reaction mixture wasstirred overnight at 60° C. The reaction mixture was concentrated invacuo and residue was partitioned between water and EtOAc. The combinedorganic layers were washed with water, brine, dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified over silica gel (20%EtOAc in CH₂Cl₂) to afford methyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pentanoate.

The following compound was synthesized using the procedure described inPreparation 48.

Preparation Structure Name 49

tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1- carboxylate

Preparation 50 tert-butyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2mmol) in DMF (25 mL) was added sodium hydride (0.33 g, 8.2 mmol) insmall portions under a stream of nitrogen. tert-Butyl 2-bromopropanoate(2.2 g, 10 mmol) was added and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water andthe aqueous layer was extracted with EtOAc. The combined organicextracts were washed with water, brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified over silica gel (0 to30% EtOAc in CH₂Cl₂) to afford tert-butyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate(0.30 g, 17.6% yield).

Preparation 516-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

In 30 mL of THF were combined4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (2.10 g, 7.77 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(2.74 g, 9.33 mmol), XPHOS (0.741 g, 1.55 mmol), and Pd₂(dba)₃ (0.356 g,0.389 mmol). The reaction mixture was sparged with argon for 1 minutebefore 2 M aqueous K₂CO₃ (15.5 mL, 31.1 mmol) was added by syringe. Thesparging was continued for 5 minutes before the reaction mixture wassealed and heated to 80° C. over the weekend. To the reaction mixturewas added 100 mL of EtOAc and 20 mL of water and the layers wereseparated. The aqueous layer was washed with EtOAc and the combinedorganic extracts were dried over MgSO₄, filtered, and concentrated. Theresidue was diluted with CH₂Cl₂ and stirred for 5 minutes, filtered anddried to6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(1.37 g, 4.91 mmol, 63.1% yield).

The following compound was synthesized according to the proceduredescribed in Preparation 51

Preparation Structure Name 52

6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine

Preparation 53 (S)-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methylmethanesulfonate

Step A: Methyl (S)-(−)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (4.6 mL,32 mmol) was dissolved in THF (125 mL) and cooled in an ice bath.Methylmagnesium bromide (23 mL, 70 mmol) was added slowly and thereaction mixture was stirred at room temperature for 30 minutes.Saturated aqueous NH₄Cl was added carefully. The reaction mixture wasextracted with EtOAc, dried over sodium sulfate, filtered andconcentrated to afford (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-ol(4.2 g, 26 mmol, 82% yield).

Step B: Anhydrous 4-methylbenzenesulfonic acid (0.226 g, 1.31 mmol) waspartially dissolved in CH₂Cl₂ (50 mL), and(S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-ol (4.2 g, 26.2 mmol) wasadded. After 1 hour at room temperature, prop-1-en-2-yl acetate (3.32mL, 30.1 mmol) was added and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with aqueousNaHCO₃ and stirred for 1 hour. The mixture was partitioned, and theorganic layer was dried over sodium sulfate and concentrated. Theresulting oil was purified over silica gel (10% EtOAc in hexanes) toafford (S)-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methyl acetate (4.0 g,19.8 mmol, 75.4% yield) as a clear, colorless oil.

Step C: (S)-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methyl acetate (4.0g, 20 mmol) was dissolved in THF (60 mL) and cooled in an ice bath.LiAlH₄ (9.9 mL, 9.9 mmol) [1M in THF] was added slowly and the reactionmixture was stirred at 0° C. for 30 minutes. Sodium sulfate decahydratewas added and the reaction mixture was stirred vigorously for 20 minutesat room temperature. The resultant suspension was filtered throughCelite® and concentrated to afford crude(S)-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methanol (3.3 g, 21 mmol,104% yield) as a clear, colorless oil.

Step D: (S)-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methanol (3.3 g, 20.6mmol) was dissolved in CH₂Cl₂ (100 mL) and cooled in ice bath.Triethylamine (4.31 mL, 30.9 mmol) was added, followed bymethanesulfonyl chloride (1.75 mL, 22.7 mmol). The ice bath was removedand the reaction mixture was warmed to room temperature. After 45minutes, the reaction mixture was partitioned between water and CH₂Cl₂.The combined organic extracts were dried over sodium sulfate, filteredand concentrated. The residue was purified over silica gel (30% EtOAc inhexanes) to afford (S)-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methylmethanesulfonate (3.6 g, 15.1 mmol, 73.3% yield) as a clear, colorlessoil.

The following compound was synthesized according to the proceduredescribed in Preparation 53.

Preparation Structure Name 54

(R)-(2,2,5,5-tetramethyl-1,3- dioxolan-4-yl)methyl methanesulfonate

Preparation 55 ((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate

Step A: (4S,5R)-Methyl 2,2,5-trimethyl-1,3-dioxolane-4-carboxylate (5.0g, 29 mmol) was dissolved in THF (100 mL) and cooled in an ice bath.LiAlH₄ (14 mL, 14 mmol) was added slowly and stirred for 30 min in icebath. Sodium sulfate decahydrate added carefully and stirred for 20minutes at room temperature. The mixture was filtered through Celite®and concentrated to afford((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)methanol (4.2 g, 29 mmol,100% yield) as a clear, colorless oil.

Step B: ((4R,5R)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)methanol (4.2 g, 28.7mmol) was dissolved in CH₂Cl₂ (100 mL) and cooled in an ice bath.Triethylamine (6.01 mL, 43.1 mmol) was added, followed bymethanesulfonyl chloride (2.45 mL, 31.6 mmol). The ice bath was removedand the reaction mixture was warmed to room temperature. After 45 min,the reaction mixture was partitioned between water and CH₂Cl₂, andcombined organic extracts were dried over sodium sulfate, filtered andconcentrated. The residue was purified over silica gel (30% EtOAc inhexanes) to afford ((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate (4.8 g, 21.4 mmol, 74.5% yield) as a clear, colorlessoil.

The following compound was synthesized according to the proceduredescribed in Preparation 55.

Preparation Structure Name 56

((4S,5S)-2,2,5-trimethyl-1,3- dioxolan-4-yl)methyl4-methylbenzenesulfonate

Preparation 57 (2,2,4-trimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate

Step A: Osmium(VIII) oxide (2.0 mL, 0.327 mmol) was added to a solutionof 4-methylmorpholine 4-oxide (8.44 g, 72.1 mmol), water (10 mL),acetone (7.5 mL) and tBuOH (6.7 mL). tert-Butyl methacrylate (5.71 mL,35.2 mmol) in acetone (10 mL) was added dropwise and the reactionmixture was stirred at room temperature over the weekend. The reactionmixture was quenched with dilute aqueous NaHSO₃. The phases wereseparated, and the organic layer was dried over sodium sulfate andconcentrated to afford crude tert-butyl 2,3-dihydroxy-2-methylpropanoate(6.2 g, 35.2 mmol, 100% yield) which was taken forward without furtherpurification.

Step B: Crude tert-butyl 2,3-dihydroxy-2-methylpropanoate (6.2 g, 35.2mmol) was dissolved in 2,2-dimethoxypropane (43.2 mL, 352 mmol) and4-methylbenzenesulfonic acid (0.909 g, 5.28 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionmixture was quenched with saturated aqueous NaHCO₃ and diluted withEtOAc. The organic layer was separated, dried over sodium sulfate,filtered and concentrated to afford tert-butyl2,2,4-trimethyl-1,3-dioxolane-4-carboxylate (5.3 g, 24.5 mmol, 69.6%yield) as a clear, colorless oil

Step C: Tert-butyl 2,2,4-trimethyl-1,3-dioxolane-4-carboxylate (5.3 g,25 mmol) was dissolved in THF (100 mL) and cooled in an ice bath. LiAlH₄(15 mL, 15 mmol) was added slowly and stirred in an ice bath for 30 min.Sodium sulfate decahydrate was added cautiously, and the reactionmixture was warmed to room temperature, stirred for 20 min, filteredthrough Celite® and concentrated to afford(2,2,4-trimethyl-1,3-dioxolan-4-yl)methanol (3.1 g, 21 mmol, 87% yield)as a clear, colorless oil.

Step D: (2,2,4-Trimethyl-1,3-dioxolan-4-yl)methanol (3.11 g, 21.3 mmol)was dissolved in CH₂Cl₂ (100 mL) and cooled in ice bath. Triethylamine(3.85 mL, 27.7 mmol) was added, followed by methanesulfonyl chloride(1.81 mL, 23.4 mmol). The ice bath was removed and the reaction mixturewas stirred for 30 min. The reaction mixture was partitioned betweenCH₂Cl₂ and water, and the combined organic extracts were dried oversodium sulfate, filtered and concentrated. The residue was purified oversilica gel (50% EtOAc in hexanes) to afford(2,2,4-trimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (4.0 g, 17.8mmol, 83.8% yield) as a clear, colorless oil.

Preparation 58 (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate

(2,2-Dimethyl-1,3-dioxan-5-yl)methanol (1.0 g, 6.84 mmol) was dissolvedin CH₂Cl₂ (30 mL) and cooled in ice bath. Triethylamine (1.14 mL, 8.21mmol) was added, followed by methanesulfonyl chloride (0.586 mL, 7.52mmol) and the reaction mixture was warmed to room temperature. Thereaction mixture was washed with 0.1 N HCl, saturated aqueous NaHCO₃,and the combined organic extracts were dried over sodium sulfate,filtered and concentrated to afford (2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate (1.5 g, 6.69 mmol, 97.8% yield) as a clear colorlessoil.

The following compounds were synthesized using the procedure describedin Preparation 58.

Preparation Structure Name 59

cis-2-phenyl-1,3-dioxan-5-yl methanesulfonate 60

2,2-dimethyl-1,3-dioxan-5-yl methanesulfonate 61

(S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate 62

(R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate 63

methyl 2,2-dimethyl-3- ((methylsulfonyl)oxy)propanoate 64

ethyl 1- (((methylsulfonyl)oxy)methyl)cyclopropanecarboxylate 65

(R)-tert-butyl 3-((tosyloxy)methyl)morpholine- 4-carboxylate 66

(S)-tert-butyl 3-((tosyloxy)methyl)morpholine-4- carboxylate 67

benzyl 3- ((tosyloxy)methyl)cyclobutanecarboxylate 68

1,1,1-trifluorobutan-2-yl methanesulfonate

Preparation 69 1-((R)-1,4-dioxaspiro[4,5]decan-2-yl)ethylmethanesulfonate

Step A: A solution of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (1.0g, 5.9 mmol) in THF (30 mL) was cooled to 0° C. and methylmagnesiumbromide (4.2 mL, 5.9 mmol) was added dropwise. The reaction mixture wasstirred for 1 hour, quenched with water and extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo to provide1-((R)-1,4-dioxaspiro[4.5]decan-2-yl)ethyl methanesulfonate. Thematerial was used in the next step without purification.

Step B: A solution of 1-((R)-1,4-dioxaspiro[4.5]decan-2-yl)ethanol (0.90g, 4.83 mmol) in CH₂Cl₂ (30 mL) was cooled to 0° C. andN-ethyl-N-isopropylpropan-2-amine (1.30 mL, 7.25 mmol) added. DMAP (1chip) was added, followed by dropwise addition of methanesulfonylchloride (0.420 mL, 5.32 mmol). The reaction mixture as stirred for 3hours. The reaction mixture was quenched with water and the layers wereseparated. The combined organic layers were washed with brine, driedover MgSO₄ and concentrated in vacuo to afford1-((R)-1,4-dioxaspiro[4.5]decan-2-yl)ethyl methanesulfonate.

The following compound was synthesized using the procedure described inPreparation 69.

Preparation Structure Name 70

1-((S)-2,2-dimethyl-1,3-dioxolan-4- yl)ethyl methanesulfonate

Preparation 71 2-(N-methylmethylsulfonamido)ethyl methanesulfonate

2-(Methylamino)ethanol (2.1 mL, 26.6 mmol) was dissolved in CH₂Cl₂ (200mL) and the flask was placed in a water bath. Triethylamine (9.3 mL,66.6 mmol) was added, followed by slow addition of methanesulfonylchloride (4.6 mL, 58.6 mmol). After 1 hour, the reaction mixture waswashed with 0.1 M HCl and saturated aqueous NaHCO₃. The combined organiclayers were dried over sodium sulfate, filtered and concentrated toafford 2-(N-methylmethylsulfonamido)ethyl methanesulfonate (5.2 g, 22.48mmol, 84.43% yield) as an oil.

Preparation 72 (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methylmethanesulfonate

Step A: Methyl tetrahydrothiopyran-4-carboxylate (1.0 g, 6.2 mmol) wasdissolved in CH₂Cl₂ (50 mL) and cooled in an ice bath.3-Chlorobenzoperoxoic acid (3.4 g, 14 mmol) was added in portions andthe reaction mixture was allowed to warm to room temperature overnight.The reaction mixture was diluted with CH₂Cl₂ and washed with saturatedaqueous NaHCO₃, and the combined organic extracts were dried over sodiumsulfate, filtered and concentrated to afford methyltetrahydro-2H-thiopyran-4-carboxylate 1,1-dioxide (1.1 g, 5.7 mmol, 92%yield) as a white solid.

Step B: Methyl tetrahydro-2H-thiopyran-4-carboxylate 1,1-dioxide (1.1 g,5.7 mmol) was dissolved in THF (50 mL) and cooled in ice bath. LiAlH₄(3.4 mL, 3.4 mmol) was added slowly and the reaction mixture was allowedto stir in ice bath for 30 minutes. Sodium sulfate decahydrate was addedin portions. The reaction mixture was allowed to warm to roomtemperature and then filtered through Celite® and concentrated to afford4-(hydroxymethyl)tetrahydro-2H-thiopyran 1,1-dioxide (0.96 g, 5.8 mmol,102% yield) as a white solid.

Step C: 4-(Hydroxymethyl)tetrahydro-2H-thiopyran 1,1-dioxide (0.90 g,5.480 mmol) was dissolved in CH₂Cl₂ (25 mL) and cooled in ice bath.Triethylamine (1.146 mL, 8.221 mmol) was added, followed bymethanesulfonyl chloride (0.5111 mL, 6.576 mmol) and ice bath removed.After 1 hour the reaction mixture was diluted with CH₂Cl₂ and washedwith 0.1 M HCl, saturated aqueous NaHCO₃ and brine, dried over sodiumsulfate, filtered and concentrated to afford(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl methanesulfonate (1.04g, 4.292 mmol, 78.32% yield) as a white solid.

Preparation 73 cis-3-(tosyloxy)cyclobutyl pivalate

Step A: To a solution of 3-oxocyclobutyl pivalate (1.0 g, 5.88 mmol) inEtOH (7.34 mL, 5.88 mmol) at 0° C. was carefully added NaBH₄ (0.333 g,8.81 mmol). The reaction mixture was stirred for 60 minutes and thenslowly quenched with a saturated aqueous NH₄Cl solution (20 mL). Thereaction mixture was extracted with CH₂Cl₂ (3×15 mL). The combinedextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford cis-3-hydroxycyclobutyl pivalate as a lightyellow oil.

Step B: To a solution of cis-3-hydroxycyclobutyl pivalate (0.830 g, 4.82mmol) in pyridine (12.0 mL, 4.82 mmol) at 0° C. was addedp-toluenesulfonyl chloride (1.84 g, 9.64 mmol). The reaction mixture wasstirred for 18 hours as the ice bath warmed to ambient temperature over2 hours. The mixture was concentrated, diluted with water and extractedwith EtOAc. The combined extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. The residual yellow oil was dissolvedin minimal EtOAc (5 mL) and the mixture was diluted with hexanes (90 mL)and cooled to −2° C. in a freezer for 3 hours. The resulting solid wasisolated by vacuum filtration and the solid was washed with hexanes anddried in vacuo providing cis-3-(tosyloxy)cyclobutyl pivalate (600 mg,38% yield) as an off-white solid.

Preparation 744-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

To6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.80 g, 1.8 mmol) was added TFA (4.1 g, 36 mmol) and the reactionmixture was stirred for 4 hours at 70° C. The TFA was removed byconcentration in vacuo. The residue was slurried in water and theaqueous layer was basified by addition of 1M NaOH. The aqueous layer wasextracted with EtOAc. The combined organic extracts were washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified over silica gel (0 to 10% MeOH in CH₂Cl₂) to afford4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.4 g, 1.2 mmol, 69% yield) as a solid. Mass spectrum (apci) m/z=322.1(M+H). ¹H NMR (d₆-DMSO) δ 13.04 (s, 1H), 9.01 (s, 1H), 8.75 (s, 1H),8.41 (m, 2H), 8.20 (m, 1H), 8.16 (d, J=2.5 Hz, 1H), 7.36 (m, 1H), 4.14(m, 1H), 1.97-1.80 (m, 4H), 0.75 (t, J=7.4 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Preparation 74.

Preparation Structure Name Data 75

4-(1-isopropyl-1H- pyrazol-4-yl)-6-(1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine Mass spectrum (apci) m/z = 294.1 (M + H) 76

4-(1-(1-phenylpropyl)- 1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 370.2(M + H) 77

4-(1-(sec-butyl)-1H- pyrazol-4-yl)-6-(1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine Mass spectrum (apci) m/z = 308.1 (M + H) 78

(S)-4-(1-(sec-butyl)-1H- pyrazol-4-yl)-6-(1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine Mass spectrum (apci) m/z = 308.1 (M + H) 79

(R)-4-(1-(sec-butyl)-1H- pyrazol-4-yl)-6-(1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine Mass spectrum (apci) m/z = 308.1 (M + H) 80

(S)-4-(1-(pentan-2-yl)- 1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 322.1(M + H) 81

(R)-4-(1-(pentan-2-yl)- 1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 322.1(M + H) 82

4-(1-(cis-2- methylcyclopentyl)-1H- pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 334.1(M + H) 83

4-(1-(2,2- dimethylcyclopentyl)-1H- pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 348.2(M + H)

The following compounds were prepared according to the proceduredescribed for Example 1 below.

Preparation Structure Name Data 84

tert-butyl 2-(4-(6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H- pyrazol-1-yl)propanoate Mass spectrum (apci) m/z =394.1 (M + H) 85

6-(1-(4-methoxybenzyl)- 1H-pyrazol-4-yl)-4-(1-(1- phenylpropyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 490.2(M + H) 86

4-(1-(sec-butyl)-1H- pyrazol-4-yl)-6-(l-(4- methoxybenzyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 428.2(M + H) 87

(S)-4-(1-(sec-butyl)-1H- pyrazol-4-yl)-6-(1-(4- methoxybenzyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 428.2(M + H) 88

(R)-4-(1-(sec-butyl)-1H- pyrazol-4-yl)-6-(l-(4- methoxybenzyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 428.2(M + H) 89

(S)-6-(1-(4- methoxybenzyl)-1H- pyrazol-4-yl)-4-(1- (pentan-2-yl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 442.2(M + H) 90

(R)-6-(1-(4- methoxybenzyl)-1H- pyrazol-4-yl)-4-(1- (pentan-2-yl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 442.2(M + H) 91

6-(1-(4-methoxybenzyl)- 1H-pyrazol-4-yl)-4-(1- (cis-2-methylcyclopentyl)-1H- pyrazol-4- yl)pyrazolo[1,5- a)pyrazine Massspectrum (apci) m/z = 454.2 (M + H) 92

4-(1-(2,2- dimethylcyclopentyl)-1H- pyrazol-4-yl)-6-(1-(4-methoxybenzyl)-1H- pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum(apci) m/z = 468.2 (M + H) 93

6-(1-(4-methoxybenzyl)- 1H-pyrazol-4-yl)-4-(1- (pentan-3-yl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 442.2(M + H) 94

4-(1-isopropyl-1H- pyrazol-4-yl)-6-(1-(4- methoxybenzyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 414.2 (M + H)

The following compounds were prepared according to Example 31 below.

Preparation Structure Name Data 95

tert-butyl 4-(2-(4-(4- (1-(pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)ethyl)piperazine-1- carboxylale Massspectrum (apci) m/z = 534.3 (M + H) 96

tert-butyl 4-(2-(4-(4- (1-isopropyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)ethyl)piperazine-1- carboxylate Massspectrum (apci) m/z = 506.3 (M + H)

SYNTHETIC EXAMPLES Example 14-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (0.750 g, 2.78 mmol),1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.887 g, 3.33 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.397g, 0.833 mmol), and Pd₂dba₃ (0.127 g, 0.139 mmol) were combined in 30 mLof dioxane. The reaction mixture was sparged with argon for 5 minutesbefore potassium carbonate (4.16 mL, 8.33 mmol) was added with stirring.The sparging was continued for another 2 minutes before the reactionvessel was sealed and then heated to 75° C. overnight. The reactionmixture was diluted with 200 mL of EtOAc and washed with 20 mL of brine.The organic layer was dried over MgSO₄, filtered, and removed underreduced pressure. The residue was purified over silica (80% EtOAc inHexanes) to afford4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.340 g, 0.957 mmol, 34.5% yield). Mass spectrum (apci) m/z=338.1(M+H). ¹H NMR (d₆-DMSO) δ 9.01 (d, J=1.0 Hz, 1H), 8.87 (s, 1H), 8.43 (s,1H), 8.37 (s, 1H), 8.18 (d, J=2.4 Hz, 1H), 8.14 (d, J=0.9 Hz, 1H), 7.40(dd, J=2.5, 1.0 Hz, 1H), 5.69 (q, J=6.1 Hz, 1H), 3.91 (s, 3H), 3.55-3.46(m, 1H), 3.33-3.24 (m, 1H), 1.72 (d, J=6.1 Hz, 3H), 1.07 (t, J=7.0 Hz,3H).

Example 24-(1-cycloheptyl-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (30 mg, 0.11 mmol) and1-cycloheptyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(64 mg, 0.22 mmol) were dissolved in K₂CO₃ (167 μL, 0.33 mmol) and THF(1 mL). Pd₂dba₃ (2.5 mg, 0.0028 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (5.3mg, 0.011 mmol) were added. The vial was sealed and heated to 70° C.overnight. The reaction mixture was cooled to room temperature, dilutedwith EtOAc, decanted, concentrated and purified over silica gel (80%EtOAc in hexanes) to afford4-(1-cycloheptyl-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(33 mg, 0.091 mmol, 82% yield) as a tan waxy solid. Mass spectrum (apci)m/z=362.2 (M+H). ¹H NMR (CDCl₃) δ 8.44 (s, 1H), 8.21 (s, 1H), 8.19 (s,1H), 8.02 (m, 1H), 7.94 (s, 2H), 6.93 (m, 1H), 4.47-4.38 (m, 1H), 3.99(s, 3H), 2.29-2.20 (m, 2H), 2.12-2.00 (m, 2H), 1.92-1.82 (m, 2H),1.76-1.55 (m, 6H).

Example 34-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)morpholine

To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.042 g, 0.131 mmol) in 1 mL of DMA was added4-(2-chloroethyl)morpholine hydrochloride (0.0486 g, 0.261 mmol) andcesium carbonate (0.170 g, 0.523 mmol) and reaction mixture was stirredovernight at 70° C. The reaction mixture was purified by reverse phasechromatography (C18, 0-50% CH₃CN/water) to afford4-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)morpholine(0.0222 g, 0.0511 mmol, 39.1% yield). Mass spectrum (apci) m/z=435.2(M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=0.8 Hz, 1H), 8.27 (s, 1H), 8.17 (s,1H), 8.06 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.97 (s, 1H), 6.95 (dd,J=2.3, 0.8 Hz, 1H), 4.32 (t, J=6.7 Hz, 2H), 4.07-3.99 (m, 1H), 3.72 (m,4H), 2.89 (t, J=6.7 Hz, 2H), 2.53 (m, 4H), 2.06-1.85 (m, 4H), 0.86 (t,J=7.4 Hz, 3H).

The following compounds were prepared according to the proceduredescribed for Example 3.

Example Structure Name Data  4

4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)-6-(1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine Mass spectrum (apci)m/z = 420.2 (M + H)  5

N,N-dimethyl-2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1- yl)acetamide Massspectrum (apci) m/z = 407.2 (M + H)  6

1-morpholino-2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1- yl)ethanone Mass spectrum(apci) m/z = 449.2 (M + H)  7

6-(1-(3- (methylsulfonyl)propyl)-1H- pyrazol-4-yl)-4-(l-(pentan-3-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine Mass spectrum (apci) m/z =442.2 (M + H)  8

5-((4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)methyl)oxazolidin-2-one Mass spectrum (apci) m/z =421.2 (M + H)  9

N-methyl-N-(2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide Mass spectrum (apci) m/z = 457.2 (M + H) 10

N,N-dimethyl-2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1- yl)ethanamine Massspectrum (apci) m/z = 393.2 (M + H) 11

4-((4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)methyl)tetrahydro-2H- thiopyran 1,1-dioxide Massspectrum (apci) m/z = 468.2 (M + H) 12

N,N-dimethyl-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)propan- 1-amine Massspectrum (apci) m/z = 407.3 (M + H) 13

3-(4-(4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol- 1-yl)thietane 1,1-dioxide Mass spectrum(apci) m/z = 426.2 (M + H) 14

(R)-2-methyl-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)propan- 1-ol Massspectrum (apci) m/z = 394.9 (M + H) 15

(S)-2-methyl-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)propan- 1-ol Massspectrum (apci) m/z = 394.2 (M + H) 16

(3-((4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)methyl)oxetan-3- yl)methanol Mass spectrum (apci)m/z = 422.2 (M + H) 17

(S)-5-((4-(4-(1-(pentan-3- yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one Mass spectrum (apci) m/z = 419.2 (M + H) 18

(R)-5-((4-(4-(1-(pentan-3- yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one Mass spectrum (apci) m/z = 419.2 (M + H) 19

3-(4-(4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol- 1-yl)propan-1-ol Mass spectrum (apci) m/z =380.2 (M + H) 20

2-(4-(4-(l-(pentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol- 1-yl)ethanol Mass spectrum (apci) m/z =366.1 (M + H) 21

(R)-4-(4-(4-(1-(sec-butyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)tetrahydro-2H-thiopyran 1,1-dioxide Mass spectrum(apci) m/z = 440.2 (M + H)

Example 226-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.042 g, 0.131 mmol) in 1 mL of CH₃CN was added (methylsulfonyl)ethene(0.00139 g, 0.0131 mmol) and2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.00 mmol) and thereaction mixture was stirred overnight at 70° C. The reaction mixturewas purified by reverse phase chromatography (C18, 0-50% CH₃CN/water) toafford6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.0397 g, 0.0929 mmol, 71.1% yield). Mass spectrum (apci) m/z=428.2(M+H). ¹H NMR (CDCl₃) δ 8.48 (s, 1H), 8.26 (s, 1h), 8.19 (s, 1H), 8.14(s, 1H), 8.04 (m, 2H), 6.97 (dd, J=2.4, 0.8 Hz, 1H), 4.70 (t, J=6.1 Hz,2H), 4.04 (m, 1H), 3.73 (t, J=6.1 Hz, 2H), 2.61 (s, 3H), 2.07-1.85 (m,4H), 0.86 (t, J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 57.

Example Structure Name Data 23

N,N-dimethyl-2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)ethanesulfonamide Mass spectrum (apci)m/z = 457.2 (M + H) 24

2-(4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)ethanesulfonamide Mass spectrum (apci) m/z =429.1 (M + H)

Example 254-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-4-y)-1H-pyrazol-4-yl)pyrazolo[1,5a]pyrazinehydrochloride

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.080 g, 0.25 mmol) in 1 mL of DMA was added tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.21 g, 0.75 mmol) andcesium carbonate (0.32 g, 1.00 mmol) and the reaction mixture wasstirred overnight at 70° C. The reaction mixture was purified oversilica gel (20 to 100% EtOAc in CH₂Cl₂) to afford tert-butyl4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.065 g, 0.13 mmol, 52% yield).

Step B: To a solution of tert-butyl4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.060 g, 0.119 mmol) in isopropyl alcohol (1 mL) was added hydrogenchloride (0.00434 g, 0.119 mmol) (1 mL of a 5 M solution in isopropylalcohol) and the reaction mixture was stirred overnight. The reactionmixture was concentrated in vacuo to afford4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (39.8 mg, 83% yield). Mass spectrum (apci) m/z=405.2(M+H). ¹H NMR (d₆-DMSO) δ 9.04 (s, 1H), 8.98 (br s, 1H), 8.74 (s, 1H),8.73 (br s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.18 (d,J=2.3 Hz, 1H), 7.38 (dd, J=2.3, 0.8 Hz, 1H), 4.57 (m, 1H), 4.14 (m, 1H),3.43 (m, 2H), 3.11 (m, 2H), 2.35-2.15 (m, 4H), 1.88 (m, 4H), 0.75 (t,J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 61.

Example Structure Name Data 26

4-(1-isopropyl-1H- pyrazol-4-yl)-6-(1- (piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5 a]pyrazine Mass spectrum (apci) m/z = 377.2(M + H) 27

(R)-4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)-6-(1- (pyrrolidin-2-ylmethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z =405.2 (M + H) 28

(S)-4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)-6-(1- (pyrrolidin-2-ylmethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z =405.2 (M + H) 29

(R)-4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)-6-(1- (piperidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 405.2(M + H) 30

(S)-3-((4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)methyl)morpholine Mass spectrum (apci) m/z =421.2 (M + H)

Example 311-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone

4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride salt (20 mg, 0.04 mmol) was stirred in CH₂Cl₂ (1 mL) andcooled in an ice bath. Triethylamine (23 μL, 0.16 mmol) was added,followed by acetic anhydride (5.9 μL, 0.06 mmol). The reaction mixturewas stirred in an ice bath for 15 minutes and then quenched with water.The layers were separated, and the organic layer was dried, filtered andconcentrated. The residue was purified over silica gel to afford1-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone(9 mg, 48% yield). Mass spectrum (apci) m/z=447.3 (M+H). ¹H NMR(d₆-DMSO) δ 8.98 (d, J=0.8 Hz, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.41 (s,1H), 8.16 (m, 2H), 7.36 (dd, J=2.3, 0.8 Hz, 1H), 4.50 (m, 2H), 4.13 (m,1H), 3.95 (m, 1H), 3.24 (m, 1H), 2.75 (td, J=12.9, 2.3 Hz, 1H), 2.10 (m,2H), 2.06 (s, 3H), 2.00-1.75 (m, 6H), 0.75 (t, J=7.4 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 31, using the appropriate anhydride, alkylsulfonate or aryl sulfonate.

Example Structure Name Data 32

6-(1-(1- (methylsulfonyl)piperidin- 4-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum(apci) m/z = 483.2 (M + H) 33

2-methoxy-1-(4-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)piperidin-1- yl)ethanone Mass spectrum(apci) m/z = 477.2 (M + H) 34

N-methyl-4-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)piperidine-1- carboxamide Mass spectrum(apci) m/z = 462.3 (M + H) 35

N,N-dimethyl-4-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)piperidine-1- carboxamide Mass spectrum(apci) m/z = 476.3 (M + H)

Example 362-amino-1-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone

Step A:4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinedihydrochloride salt (30 mg, 0.063 mmol) was stirred in CH₂Cl₂ (1 mL)and Et₃N (52 μL, 0.38 mmol) was added, followed by2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)acetate (34 mg,0.13 mmol). The reaction mixture was stirred at room temperature for 1hour. Water (0.1 mL) was added and the reaction mixture wasconcentrated. The residue was purified by reverse phase chromatography(5-95% CH₃CN in water) to afford tert-butyl(2-oxo-2-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)carbamate(25 mg, 71% yield).

Step B: tert-Butyl(2-oxo-2-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)carbamate(24 mg, 0.042 mmol) was dissolved in CH₂Cl₂ (2 mL) and 5.5 M HCl inisopropyl alcohol (155 μL, 0.85 mmol) was added. The reaction mixturewas stirred at room temperature for 3 hours. The solvent was evaporatedto afford2-amino-l-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone(21.5 mg, 94% yield). Mass spectrum (apci) m/z=462.2 (M+H). ¹H NMR(d₆-DMSO) δ 9.00 (d, J=0.8 Hz, 1H), 8.74 (s, 1H), 8.45 (s, 1H), 8.40 (s,1H), 8.18 (s, 1H), 8.17 (d, J=2.5 Hz, 1H), 8.12 (m, 2H), 7.37 (dd,J=2.5, 1.0 Hz, 1H), 4.56 (tt, J=11.1, 4.1 Hz, 1H), 4.49 (m, 1H), 4.14(m, 1H), 3.95 (m, 4H), 3.26 (m, 1H), 2.93 (m, 1H), 2.15 (m, 2H), 2.01(m, 1H), 1.97-1.80 (m, 4H), 0.75 (t, J=7.2 Hz, 6H).

Example 376-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

Step A:4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.50 g, 1.6 mmol) was dissolved in DMF (8 mL). tert-Butyl3-((methylsulfonyl)oxy)azetidine-1-carboxylate (0.39 g, 1.6 mmol) andCs₂CO₃ (1.01 g, 3.1 mmol) were added and the reaction mixture was heatedto 70° C. overnight. The reaction mixture was poured into water (100 mL)and extracted with EtOAc. The combined organic extracts were washed withwater, dried over sodium sulfate, filtered and concentrated. The residuewas purified over silica gel (10-80% EtOAc in hexanes) to affordtert-butyl3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(0.55 g, 74% yield).

Step B: tert-Butyl3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(0.5 g, 1.1 mmol) was dissolved in CH₂Cl₂. TFA (10 mL) was added and thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated, partitioned between saturated aqueousNaHCO₃ and 5% isopropyl alcohol in CHCl₃. The organic layer was driedover sodium sulfate, filtered and concentrated to afford6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(380 mg, 96% yield) as a tan solid. Mass spectrum (apci) m/z=377.2(M+H).

Step C:6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(30 mg, 0.0797 mmol) was dissolved in THF (0.5 mL) and triethylamine(13.3 μL, 0.0956 mmol) was added, followed by methanesulfonyl chloride(6.83 μL, 0.0877 mmol), and the reaction mixture was stirred for 15minutes. The reaction mixture was diluted with water and extracted withDCM and then with EtOAc. The combined organic extracts were dried,filtered and concentrated. The residue was purified over silica gel (90%EtOAc in hexane) to afford6-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(25 mg, 0.0550 mmol, 69.0% yield) as a pale yellow solid. Mass spectrum(apci) m/z=455.2 (M+H). ¹H NMR (CDCl₃) δ 8.47 (d, J=1.0 Hz, 1H), 8.27(s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 8.04 (m, 2H), 6.97 (dd, J=2.3, 1.0Hz, 1H), 5.17 (m, 2H), 4.53-4.40 (m, 4H), 4.03 (m, 1H), 3.06 (m, 1H),2.05-1.85 (m, 4H), 0.86 (t, J=7.4 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 80.

Example Structure Name Data 38

1-(3-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1- yl)ethanone Mass spectrum(apci) m/z = 419.2 (M + H) 39

N-methyl-3-(4-(4-(1- (pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidine-1- carboxamide Mass spectrum(apci) m/z = 434.2 (M + H) 40

N,N-dimethyl-3-(4-(4-(1- (pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidine-1- carboxamide Mass spectrum(apci) m/z = 448.2 (M + H) 41

Bis-N,N-dimethyl-P-(3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1-yl)phosphonic amide Mass spectrum (apci) m/z = 511.2 (M + H) 42

2-methyl-1-(3-(4-(4-(1- (pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1- yl)propan-1-one Massspectrum (apci) m/z = 447.3 (M + H) 43

cyclopropyl(3-(4-(4-(1- (pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-l- yl)methanone Mass spectrum(apci) m/z = 445.2 (M + H)

Example 442-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)butanoicacid

To a solution of tert-butyl2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)butanoate(0.20 g, 0.49 mmol) in THF (5 mL) was added lithium hydroxide (2.5 mL,4.9 mmol) and the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated to remove the THF,and the aqueous layer was acidified with HCl (1M). The aqueous layer wasextracted into EtOAc, and the organic layer was washed with brine, driedover MgSO₄ and concentrated in vacuo to afford2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)butanoicacid (0.140 g, 82% yield). Mass spectrum (apci) m/z=350.1 (M−H). ¹H NMR(d₆-DMSO) δ 13.16 (s, 1H), 8.96 (d, J=0.8 Hz, 1H), 8.75 (s, 1H), 8.37(s, 1H), 8.32 (s, 1H), 8.14 (d, J=2.4 Hz, 1H), 8.09 (s, 1H), 7.32 (dd,J=2.4, 0.8 Hz, 1H), 5.02 (dd, J=9.6, 5.7 Hz, 1H), 3.88 (s, 3H),2.30-2.15 (m, 2H), 0.81 (t, J=7.2 Hz, 3H).

Example 452-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)butan-1-ol

To a solution of tert-butyl2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)butanoate(0.05 g, 0.12 mmol) in isopropyl alcohol (1 mL) was added NaBH₄ (0.014g, 0.37 mmol) and the reaction mixture was stirred at room temperaturefor 5 hours. The reaction mixture was poured into water and extractedinto EtOAc. The organic layer was washed with brine, dried over MgSO₄and concentrated in vacuo. The residue was purified over silica gel(0-10% MeOH in CH₂Cl₂) to afford2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)butan-1-ol(0.013 g, 0.039 mmol, 31% yield). Mass spectrum (apci) m/z=338.1 (M+H).¹H NMR (d₆-DMSO) δ 8.39 (d, J=1.0 Hz, 1H), 8.23 (s, 1H), 8.22 (s, 1H),8.00 (d, J=2.3 Hz, 1H), 7.90 (m, 2H), 6.89 (dd, J=2.4, 1.0 Hz, 1H), 4.24(m, 1H), 4.10-3.98 (m, 2H), 3.97 (s, 3H), 2.12-1.90 (m, 2H), 0.95 (t,J=7.4 Hz, 3H).

The following compounds were prepared according to the proceduredescribed for Example 45.

Example Structure Name Data 46

2-(4-(6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)propan-1-ol Mass spectrum (apci) m/z = 324.1 (M + H) 47

3-(4-(6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)pentan-1-ol Mass spectrum (apci) m/z = 352.1 (M + H)

Example 484-(1-(3-ethyl-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

Step A: 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (1.0 g, 3.7 mmol), tert-butyl3-(2-ethoxy-2-oxoethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(2.01 g, 4.6 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPHOS) (353 mg,0.74 mmol) and Pd₂(dba)₃ (170 mg, 0.19 mmol) were combined in THF (15mL) and treated with K₂CO₃ (7.4 mL, 2.0 M, 14.8 mmol). The reactionvessel was sealed, placed into an 80° C. oil bath and stirred overnight.The reaction mixture was filtered through GF/F paper with EtOAc andwashed with water. The filtrate layers were separated and the aqueouslayer was extracted with EtOAc (2×50 mL). The combined organic phaseswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified over silica gel (20%acetone/CH₂Cl₂) to afford tert-butyl3-(2-ethoxy-2-oxoethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(1.47 g, 78.3% yield) as a beige solid.

Step B: A solution of tert-butyl3-(2-ethoxy-2-oxoethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(1.47 g, 2.9 mmol) in CH₂Cl₂ (20 mL) was treated with 5-6 NHCl/isopropyl alcohol (10 mL). The reaction mixture was allowed to stirat room temperature overnight. The reaction mixture was concentrated anddried in vacuo to afford ethyl2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetatedihydrochloride (1.56 g, 112% yield) as a yellow solid.

Step C: To a suspension of ethyl2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetatedihydrochloride (1.39 g, 2.9 mmol) in CH₂Cl₂ (50 mL) was addedtriethylamine (2.02 mL, 14.5 mmol) and the resulting solution cooled to0° C. and treated dropwise with trifluoromethanesulfonyl chloride (340μL, 3.19 mmol). The reaction mixture was stirred 0° C. for 2 hours. Thereaction mixture was treated with trifluoromethanesulfonyl chloride (200μL) and stirred for an additional 30 minutes. The reaction mixture waspartitioned between saturated aqueous NaHCO₃ (50 mL) and CH₂Cl₂ (50 mL)and the aqueous layer was extracted with CH₂Cl₂. The combined organicphases were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to afford ethyl2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)acetate(1.54 g, 98.6% yield) as a beige foam.

Step D: To a solution of ethyl2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)acetate(1.0 g, 1.86 mmol) in THF (50 mL) at 0° C. was added LiAlH₄ (1.11 mL,1.0 M, 1.11 mmol) dropwise over 3 minutes. After 1 hour, 0.5 mL ofLiAlH₄ was added and the reaction mixture was stirred for 10 minutes.The reaction mixture was quenched with sodium sulfate decahydrate,stirred at room temperature for 30 minutes and then filtered throughGF/F paper and concentrated. The residue was purified over silica gel(2.5% MeOH in CH₂Cl₂) to afford2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)ethanol(394 mg, 42.7% yield) as a white solid.

Step E:2-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)ethanol(50 mg, 0.10 mmol) and perbromomethane (67 mg, 0.20 mmol) were dissolvedin CH₂Cl₂ (1 mL). Triphenylphosphine (53 mg, 0.20 mmol) was added andthe reaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was purified directly over silica gel (70% EtOAc inhexanes) to afford crude4-(1-(3-(2-bromoethyl)-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(81 mg, 0.14 mmol, 144% yield) with some P(O)Ph₃.

Step F:4-(1-(3-(2-Bromoethyl)-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(56 mg, 0.10 mmol) was dissolved in THF (1 mL) and potassium2-methylpropan-2-olate (200 μL, 0.20 mmol) was added. The reactionmixture was stirred at room temperature for 15 minutes. The reactionmixture was quenched with aqueous NH₄OAc. The organic layer wasseparated, dried over sodium sulfate, filtered and concentrated. Theresidue was purified over silica gel (80% EtOAc in hexanes), followed byreverse phase chromatography (C18, 10-95% CH₃CN in water) to afford6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(1-((trifluoromethyl)sulfonyl)-3-vinylazetidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(18 mg, 0.038 mmol, 38% yield) as a white foam.

Step G:6-(1-Methyl-1H-pyrazol-4-yl)-4-(1-(1-((trifluoromethyl)sulfonyl)-3-vinylazetidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(18 mg, 0.0376 mmol) was dissolved in MeOH/EtOAc (2:1) and 10% Pd/C wasadded and stirred under a hydrogen atmosphere for 1 hour. The reactionmixture was filtered through Celite® and concentrated to afford4-(1-(3-ethyl-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(14.8 mg, 0.0308 mmol, 81.9% yield) as a tan solid. Mass spectrum (apci)m/z=481.1 (M+H). ¹H NMR (CDCl₃) δ 8.48 (d, J=1.0 Hz, 1H), 8.31 (s, 1H),8.21 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 6.93(dd, J=2.3, 1.0 Hz, 1H), 4.86 (d, J=8.6 Hz, 2H), 4.38 (d, J=8.6 Hz, 2H),4.00 (s, 3H), 2.36 (q, J=7.2 Hz, 3H).

Example 496-(1-methyl-1H-pyrazol-4-yl)-4-(1-(1-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

6-(1-Methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.100 g, 0.377 mmol) and methylenecyclopentane (0.992 mL, 9.42 mmol)were combined in 3 mL of TFA. The reaction mixture began to reflux uponaddition. The reaction mixture was concentrated and the residue waspartitioned between EtOAc (50 mL) and 1 M NaOH (20 mL). The organiclayer was washed with water and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified over silica gel (10% acetone inCH₂Cl₂) to afford6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(1-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.068 g, 0.194 mmol, 51.4% yield). Mass spectrum (apci) m/z=348.2(M+H). ¹H NMR (CDCl₃) δ 8.44 (d, J=0.8 Hz, 1H), 8.28 (s, 1H), 8.23 (s,1H), 8.02 (d, J=2.3 Hz, 1H), 7.94 (s, 2H), 6.93 (dd, J=2.3, 0.8 Hz, 1H),3.98 (s, 3H), 2.47 (m, 2H), 1.99 (m, 2H), 1.84 (m, 4H), 1.68 (s, 3H).

The following compound was prepared according to the procedure describedfor Example 49.

Example Structure Name Data 50

6-(1-methyl-1H-pyrazol- 4-yl)-4-(1-(3- methylpentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Mass spectrum (apci) m/z = 350.2 (M + H).

Example 51(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentyl)methanol

Step A: A solution of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (0.565 g, 2.09 mmol), methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopentanecarboxylate(0.670 g, 2.09 mmol), and K₂CO₃ (4.18 mL, 8.37 mmol) in dioxane 50 mLwas degassed with nitrogen for 5 minutes. Pd₂(dba)₃ (0.192 g, 0.209mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.200g, 0.418 mmol) were added and the reaction mixture was degassed for 5minutes and then heated to 80° C. overnight. The reaction mixture waspartitioned between water (50 mL) and EtOAc (100 mL). The organic layerwas washed with brine, dried over MgSO₄ and concentrated. The residuewas purified by reverse phase chromatography (C18, 5 to 95% CH₃CN inwater) to afford methyl2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentanecarboxylate(0.40 g, 48.8% yield).

Step B: Methyl2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentanecarboxylate(0.150 g, 0.38 mmol) and 4 mL of THF were combined and cooled to −40° C.LiAlH₄ (0.38 mL, 0.38 mmol) was added slowly and the reaction mixturewas stirred for 1 hour. To the cold reaction mixture was added excesssodium sulfate decahydrate and the reaction mixture was stirred andallowed to warm to room temperature. After 1 hour the reaction mixturewas diluted with EtOAc (50 mL), filtered through a nylon membrane andconcentrated to afford(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentyl)methanol(0.118 g, 0.299 mmol, 78% yield). Mass spectrum (apci) m/z=364.1 (M+H).¹H NMR (CDCl₃) δ (1:1 mix of diastereomers) 8.41 (d, J=1.0 Hz, 1H), 8.25(s, 1H), 8.21 (s, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.91 (m, 2H), 6.90 (dd,J=2.5, 1.0 Hz, 1H), 4.57 (q, J=8.0 Hz, 1H), 4.41 (q, J=8.2 Hz, 0.5H),4.10 (m, 0.5H), 3.96 (s, 3H), 3.73 (m, 1H), 3.65 (m, 1H), 2.54 (m, 1H),2.42-2.20 (m, 2H), 2.14-1.45 (m, 5H).

Example 526-(1-methyl-1H-pyrazol-4-yl)-4-(1-(2-methylcycloheptyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(50 mg, 0.19 mmol) and 2-methylcycloheptyl methanesulfonate (58 mg, 0.28mmol) in DMA (2 mL) was treated with cesium carbonate (123 mg, 0.38mmol) and then stirred at 80° C. in a sealed tube for 24 hours. Thereaction mixture was partitioned between water (30 mL) and EtOAc (20 mL)and the aqueous layer was extracted with EtOAc. The combined organicphases were washed with water and brine, then dried over Na₂SO₄,filtered and concentrated. The residue was purified over silica gel (10%acetone/CH₂Cl₂) to afford6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(2-methylcycloheptyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.035 g, 49% yield). Mass spectrum (apci) m/z=376.2 (M+H). ¹H NMR(CDCl₃) δ (1:1 mixture of diastereomers) 8.44 (m, 1H), 8.22 (s, 1H),8.17 (d, J=2.2 Hz, 1H), 8.02 (dd, J=2.3, 1.2 Hz, 1H), 7.94 (s, 2H), 6.93(m, 1H), 4.55 (dt, J=10.2, 5.3 Hz, 0.5H), 3.99 (s, 3H), 3.93 (td,J=10.0, 3.7 Hz, 0.5H), 2.45-2.20 (m, 3H), 1.95-1.40 (m, 9H), 1.25 (d,J=5.5 Hz, 1.5H), 0.80 (d, J=6.6 Hz, 1.5H), 0.74 (d, J=7.0 Hz, 1.5H).

Example 532-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentanol

Step A: In 1 mL of acetonitrile were combined6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.025 g, 0.0942 mmol), 2-chlorocyclopentanone (0.0168 g, 0.141 mmol),and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0281 mL, 0.188 mmol) at roomtemperature. The reaction mixture was sealed under nitrogen and heatedto 80° C. overnight. The reaction mixture was concentrated and purifiedover silica gel (20% acetone in CH₂Cl₂) to2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentanone(14 mg, 38% yield).

Step B: In 1 mL of MeOH were combined2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentanone(0.012 g, 0.035 mmol) and NaBH₄ (0.0039 g, 0.10 mmol) at 0° C. Thereaction mixture was allowed to warm to room temperature and stirred for3 hours. The reaction mixture was quenched with 3 drops of 50% NaOH inwater. After 20 minutes the reaction mixture was quenched with 3 dropsof TFA and purified by reverse phase chromatography (C18, 5 to 95% CH₃CNin water with 0.1% TFA) to afford2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentanol(20 mg, 166% yield) as a mixture of diastereomers. Mass spectrum (apci)m/z=350.2 (M+H). ¹H NMR (CDCl₃) δ 8.46 (m, 1H), 8.25 (m, 2H), 8.03 (d,J=2.5 Hz, 1H), 7.94 (m, 2H), 6.92 (m, 1H), 5.49 (m, 0.5H), 4.92 (m, 1H),4.45 (m, 0.5H), 3.99 (m, 4H), 2.83 (m, 0.5H), 2.51-1.85 (m, 4.5H),1.40-1.20 (m, 2H).

Example 54(R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.56 g, 1.7 mmol) in DMF (3 mL) under nitrogen was added Cs₂CO₃ (1.1 g,3.5 mmol) followed by (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane(0.52 g, 3.5 mmol) and the reaction mixture was heated to 80° C.overnight. The reaction mixture was diluted with EtOAc and washed withwater, brine, dried over MgSO₄ and concentrated in vacuo. The resultingmaterial was purified over silica gel (0-70% EtOAc/CH₂Cl₂) to afford(R)-6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine.

Step B: To(R)-6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.4 g, 0.92 mmol) in isopropyl alcohol (10 mL) was added 4 drops of 12MHCl and the reaction mixture was heated to 55° C. for 2 hours. Thereaction mixture was concentrated in vacuo and the residue was taken upin water. The water was made basic using 1N NaOH and the aqueous layerwas extracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedover silica gel (0-10% MeOH/CH₂Cl₂) to afford(R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[15-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(0.25 g, 0.63 mmol, 69% yield). Mass spectrum (apci) m/z=396.2 (M+H). ¹HNMR (d₆-DMSO) δ 9.01 (d, J=1.0 Hz, 1H), 8.74 (s, 1H), 8.40 (s, 1H), 8.36(s, 1H), 8.17 (m, 2H), 7.37 (dd, J=2.5, 1.0 Hz, 1H), 5.05 (d, J=5.3 Hz,1H), 4.78 (t, J=5.9 Hz, 1H), 4.30 (dd, J=13.7, 3.9 Hz, 1H), 4.15 (m,1H), 4.06 (dd, J=13.7, 7.8 Hz, 1H), 3.90 (m, 1H), 3.46-3.34 (m, 2H),2.00-1.79 (m, 4H), 0.76 (t, J=7.4 Hz, 6H).

Example 55 (S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolor[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.5 g, 2 mmol) in DMF (5 mL) was added(R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.5 g, 3 mmol) andCs₂CO₃ (1 g, 3 mmol) and the reaction mixture was heated to 70° C.overnight. The reaction mixture was poured into water and extracted intoEtOAc. The combined organic phases were washed with brine, dried overMgSO₄ and concentrated in vacuo. The residue was purified over silicagel (0-70% EtOAc in hexanes) to afford(S)-6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.4 g, 0.9 mmol, 59% yield).

Step B: To a solution of(S)-6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.4 g, 0.918 mmol) in isopropyl alcohol (10 mL) was added 4 drops ofHCl and the reaction mixture was heated to 60° C. for 2 hours. Thereaction mixture was concentrated and the residue was partitionedbetween EtOAc and 1N NaOH. The combined organic phases were separated,washed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified over silica gel (1-10% MeOH in CH₂Cl₂) to afford asolid, which was triturated with methyl tert-butyl ether to afford(S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(0.118 g, 0.298 mmol, 32.5% yield). Mass spectrum (apci) m/z=396.2(M+H). ¹H NMR (d₆-DMSO) δ 9.01 (d, J=0.8 Hz, 1H), 8.74 (s, 1H), 8.40 (s,1H), 8.36 (s, 1H), 8.17 (m, 2H), 7.37 (dd, J=2.5, 1.0 Hz, 1H), 5.05 (d,J=5.3 Hz, 1H), 4.78 (t, J=5.7 Hz, 1H), 4.30 (dd, J=13.7, 3.9 Hz, 1H),4.15 (m, 1H), 4.06 (dd, J=13.7, 7.8 Hz, 1H), 3.90 (m, 1H), 3.46-3.34 (m,2H), 2.00-1.79 (m, 4H), 0.76 (t, J=7.4 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 55.

Example Structure Name Data 56

(S)-3-methyl-1-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butane-2,3- diol Mass spectrum (apci)m/z = 424.2 (M + H) 57

(R)-3-methyl-1-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butane-2,3- diol Mass spectrum (apci)m/z = 424.2 (M4H) 58

3-(4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Mass spectrum (apci) m/z = 396.2(M + H) 59

(2R,3R)-1-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-l-yl)butane-2,3- diol Mass spectrum (apci)m/z = 410.2 (M + H) 60

2-methyl-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H) 61

2-((4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[l,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)methyl)propane-1,3-diol Mass spectrum (apci) m/z= 410.2 (M + H) 62

(S)-4-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)butane-1,2-diol Mass spectrum (apci) m/z = 410.2(M + H) 63

4-(4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)butane-1,3-diol Mass spectrum (apci) m/z = 410.2(M + H) 64

(R)-4-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)butane-1,2-diol Mass spectrum (apci) m/z = 410.2(M + H) 65

(2S,3S)-1-(4-(4-(1-(pentan- 3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 6-yl)-1H-pyrazol-1- yl)butane-2,3-diol Massspectrum (apci) m/z = 410.2 (M + H) 66

(2R)-3-(4-(4-(1-(1- phenylpropyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 444.2 (M + H) 67

(2R)-3-(4-(4-(1-(sec- butyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Mass spectrum (apci) m/z = 382.2(M + H) 68

(R)-3-(4-(4-(1-((S)-sec- butyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Mass spectrum (apci) m/z = 382.2(M + H) 69

(R)-3-(4-(4-(1-((R)-sec- butyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Mass spectrum (apci) m/z = 382.2(M + H) 70

(S)-3-(4-(4-(1-((S)-sec- butyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)propane-1,2-diol hydrochloride Mass spectrum(apci) m/z = 382.2 (M + H) 71

(S)-3-(4-(4-(1-((R)-sec- butyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Mass spectrum (apci) m/z = 382.2(M + H) 72

(R)-3-(4-(4-(1-((S)-pentan- 2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Massspectrum (apci) m/z = 396.2 (M + H) 73

(R)-3-(4-(4-(1-((R)-pentan- 2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Massspectrum (apci) m/z = 396.2 (M + H) 74

(S)-3-(4-(4-(1-((R)-pentan- 2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Massspectrum (apci) m/z = 396.2 (M + H) 75

(R)-3-(4-(4-(1-((S)-4- methylpentan-2-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H) 76

(S)-3-(4-(4-(1-((S)-4- methylpentan-2-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H) 77

(R)-3-(4-(4-(1-((R)-4- methylpentan-2-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H) 78

(S)-3-(4-(4-(1-((R)-4- methylpentan-2-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H) 79

(2R)-3-(4-(4-(1-(1-(3,3- difluorocyclobutyl)propyl)- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 6-yl)-1H-pyrazol-1- yl)propane-1,2-diol Massspectrum (apci) m/z = 458.2 (M + H) 80

(R)-3-(4-(4-(1-((S)-3- methylbutan-2-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 396.2 (M + H)

Example 812-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol

To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(200 mg, 0.62 mmol) in DMF (2 mL) was added Cs₂CO₃ (1.0 g, 3.1 mmol) and2,2-dimethyl-1,3-dioxan-5-yl methanesulfonate (262 mg, 1.2 mmol) and thereaction mixture was heated to 80° C. overnight. The reaction mixturewas poured into water and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified over silica gel (0-100% EtOAc in CH₂Cl₂) to afford6-(1-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.2 g, 0.46 mmol, 74% yield).

To a solution of6-(1-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.18 g, 0.41 mmol) in isopropyl alcohol (10 mL) was added 2 drops of12M HCl and the reaction mixture was heated to 80° C. for 1 hour. Thereaction was concentrated in vacuo and the material partitioned betweensaturated aqueous NaHCO₃ and EtOAc. The organic layer was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified over silica gel (0-10% MeOH in CH₂Cl₂) to afford2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol(0.13 g, 0.33 mmol, 80% yield). Mass spectrum (apci) m/z=396.2 (M+H). ¹HNMR (d₆-DMSO) δ 8.99 (d, J=1.0 Hz, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.37(s, 1H), 8.16 (m, 2H), 7.36 (dd, J=2.5, 1.0 Hz, 1H), 4.93 (t, J=5.5 Hz,2H), 4.30 (pentet, J=6.5 Hz, 1H), 4.15 (m, 1H), 3.79 (m, 4H), 1.99-1.79(m, 4H), 0.75 (t, J=7.4 Hz, 6H).

Example 82(S)-2-(4-(4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol

Step A: To a slurry of(S)-4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.10 g, 0.31 mmol) in DMF (0.5 mL) was added 2-phenyl-1,3-dioxan-5-ylmethanesulfonate (0.16 g, 0.62 mmol) and Cs₂CO₃ (0.20 g, 0.62 mmol) andthe reaction mixture was heated to 70° C. overnight. The reactionmixture was partitioned between EtOAc and water. The combined organicphases were separated and washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified over silica gel(0-100% EtOAc/CH₂Cl₂) to afford(S)-4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)-6-(1-(2-phenyl-1,3-dioxan-5-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.10 g, 0.21 mmol, 66% yield).

Step B: To a solution of(S)-4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)-6-(1-(2-phenyl-1,3-dioxan-5-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.10 g, 0.21 mmol) in isopropyl alcohol (10 mL) were added 2 drops ofHCl and the reaction mixture was heated to 60° C. for 2 hours. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between EtOAc and 0.1N NaOH. The combined organic phaseswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified over silica gel (0-10% MeOH/CH₂Cl₂) toafford(S)-2-(4-(4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol(0.009 g, 0.023 mmol, 11% yield). Mass spectrum (apci) m/z=396.2 (M+H).¹H NMR (CDCl₃) δ 8.41 (d, J=1.0 Hz, 1H), 8.20 (s, 2H), 8.12 (s, 1H),8.01 (d, J=2.5 Hz, 1H), 7.96 (s, 1H), 6.94 (dd, J=2.3, 0.8 Hz, 1H),4.48-4.36 (m, 2H), 4.17-4.11 (m, 4H), 1.99 (m, 1H), 1.79 (m, 1H), 1.59(d, J=6.8 Hz, 3H), 1.37-1.18 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).

The following compounds were prepared according to the proceduredescribed for Example 82.

Example Structure Name Data 83

(R)-2-(4-(4-(1-(pentan-2- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Mass spectrum (apci)m/z = 396.2 (M + H) 84

(S)-2-(4-(4-(1-(sec- butyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Mass spectrum (apci)m/z = 382.2 (M + H) 85

(R)-2-(4-(4-(1-(sec- butyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Mass spectrum (apci)m/z = 382.2 (M + H) 86

(S)-3-(4-(4-(1-((S)- pentan-2-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 396.2 (M + H) 87

(S)-2-(4-(4-(1-(4- methylpentan-2-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Mass spectrum (apci)m/z = 410.2 (M + H) 88

(R)-2-(4-(4-(1-(4- methylpentan-2-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Mass spectrum (apci)m/z = 410.2 (M + H)

Example 89(2S,3S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol

Step A: To4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.2 g, 0.6 mmol) was added Cs₂CO₃ (0.4 g, 1 mmol) followed by theaddition of 8 mL of DMF. To the reaction mixture was added1-((R)-1,4-dioxaspiro[4.5]decan-2-yl)ethyl methanesulfonate (0.3 g, 1mmol) and the reaction mixture was stirred under N₂ at 80° C. overnight.The reaction mixture was cooled and diluted with water (750 mL). Theaqueous layer was extracted twice with methyl tert-butyl ether. Thecombined methyl tert-butyl ether layers were back extracted with waterand brine, dried over MgSO₄ and concentrated in vacuo The crude materialwas purified over silica gel (20-70% EtOAc in CH₂Cl₂) to afford 2products. The higher eluting spot (Peak A) was6-(1-((R)-1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.040 g, 0.082 mmol) and the lower eluting spot (Peak B) was6-(1-(1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.1 g, 0.2 mmol, 33% yield).

Step B: To a solution of6-(1-((S)-1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.07 g, 0.14 mmol) in isopropyl alcohol (50 mL) was added 1 drop ofconcentrated HCl and the reaction mixture was heated to 60° C. for 2hours. The reaction mixture was concentrated in vacuo and the resultingmaterial was partitioned between 1N NaOH and EtOAc. The layers wereseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine and dried over MgSO₄ andconcentrated in vacuo. The residue was purified over silica gel (0-10%MeOH in CH₂Cl₂) to afford(2S,3S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol(isolated “Peak A”) (0.030 g, 0.073 mmol, 51% yield). Mass spectrum(apci) m/z=410.2 (M+H). ¹H NMR (CDCl₃) δ 8.43 (d, J=0.8 Hz, 1H), 8.24(s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 8.01 (d, J=2.3, Hz, 1H), 7.91 (s,1H), 6.93 (dd, J=2.3, 0.8 Hz, 1H), 4.58 (m, 1H), 4.02 (septet, J=4.5 Hz,1H), 3.95 (q, J=5.1 Hz, 1H), 3.59 (dd, J=11.5, 5.6 Hz, 1H), 3.52 (dd,J=11.3, 5.3 Hz, 1H), 2.05-1.84 (m, 4H), 1.65 (d, J=7.0 Hz, 3H), 0.85 (t,J=7.4 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 89.

Example Structure Name Data 90

(2S,3R)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H) 91

(2R,3S)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H) 92

(2R,3R)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butane-1,2- diol Mass spectrum (apci)m/z = 410.2 (M + H)

Examples 93 and 94(R)-3-(4-(4-(1-((1R,2S)-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-dioland(R)-3-(4-(4-(1-((1S,2R)-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: A round bottom flask equipped with a stir bar was charged with4-(1-(cis-2-methylcyclopentyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.057 g, 0.171 mmol) and 2 mL of DMA. To this was added(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.034 g, 0.222 mmol)and cesium carbonate (0.11 g, 0.342 mmol). The reaction mixture washeated to 70° C. After about 2.5 hours, another 0.5 equivalents of(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane was added. After another5 hours, the reaction mixture was allowed to cool to room temperatureand diluted with water. The reaction mixture was extracted with EtOAc,and the combined organic extracts were washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The crudematerial was purified by preparative TLC (2×0.5 mm plates, 1:1 ethylacetate:Hexane, developed two times) to afford6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-((1R,2S)-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(17 mg, 22% yield).

Step B: A microwave pressure tube containing6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(cis-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.017 g, 0.038 mmol) was charged with 1 mL of isopropyl alcohol and acouple of drops of concentrated HCl. The tube was sealed and warmed to60° C. for 2.5 hours. The reaction mixture was concentrated underreduced pressure and the crude material was purified by chiralchromatography (Chiral Tech IA 4.6 mm×450 mm, 5 micron, 15% EtOH inhexanes, 1 mL/min) to afford the title compounds as isolateddiastereomers. Peak A: retention time=11.3 min; Mass spectrum (apci)m/z=408.2 (M+H). Peak B: retention time=13.7 min; Mass spectrum (apci)m/z=408.2 (M+H).

Examples 95 and 96(R)-3-(4-(4-(1-((S)-2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-dioland(R)-3-(4-(4-(1-((R)-2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: A suspension of4-(1-(2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(123 mg, 0.354 mmol),(S)-(−)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (53.2 μL, 0.389mmol), Cs₂CO₃ (231 mg, 0.708 mmol) in DMF (1770 L, 0.354 mmol) washeated at 60° C. overnight. The mixture was partitioned between EtOAcand water. The aqueous layer was extracted with EtOAc. The combinedorganic layers were dried over sodium sulfate and concentrated. Theresidue was purified by reverse phase chromatography (5 to 95% CH₃CN inwater) to afford6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(88 mg, 54% yield).

Step B: To a solution of6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(88 mg, 0.19 mmol) in methanol was added 3 drops of concentrated HCl andthe reaction mixture was heated at 80° C. overnight. The reactionmixture was concentrated and purified by chiral chromatography (ChiralTech IA column, 4.6 mm×250 mm, 5 micron, 30% EtOH in hexanes, 1 mL/min)to afford 2 diastereomers. The stereochemistry was arbitrarily assigned.Peak A: retention time=24.6 min; Mass spectrum (apci) m/z=422.2; (M+H).¹H NMR (CDCl₃) δ 8.43 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 8.02 (m, 2H),7.98 (s, 1H), 6.92 (dd, J=2.3, 0.8 Hz, 1H), 4.34 (m, 3H), 4.17 (br s,1H), 3.70 (m, 3H), 2.64 (br s, 1H), 2.50-2.31 (m, 2H), 2.07-1.95 (m,1H), 1.90-1.75 (m, 2H), 1.70-1.57 (m, 2H), 1.17 (s, 3H), 0.73 (s, 3H).Peak B: retention time=27.6 min; Mass spectrum (apci) m/z=422.3 (M+H);¹H NMR (CDCl₃) δ 8.44 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 8.03 (m, 2H),7.99 (s, 1H), 6.93 (dd, J=2.3, 0.8 Hz, 1H), 4.34 (m, 3H), 4.17 (br s,1H), 3.68 (br s, 2H), 3.57 (br s, 1H), 2.54-2.30 (m, 3H), 2.07-1.95 (m,1H), 1.90-1.75 (m, 2H), 1.67-1.57 (m, 2H), 1.17 (s, 3H), 0.73 (s, 3H).

Example 97N-isopropyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)acetamide

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.060 g, 0.187 mmol) in 0.5 mL of DMA was added cesium carbonate (0.243g, 0.747 mmol) and methyl 2-bromoacetate (0.0344 mL, 0.373 mmol) and thereaction mixture was stirred for 4 hours at 70° C. The reaction mixturewas purified by reverse phase chromatography (C18; 0 to 50% CH₃CN inwater) to afford methyl2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)acetate(65 mg, 88% yield).

Step B: To a solution of methyl2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)acetate(0.0650 g, 0.165 mmol) in THF (2 mL) was added 1M lithium hydroxide(0.661 mL, 0.661 mmol) and the reaction mixture was stirred for 4 hoursat room temperature. The combined organic phases were concentrated invacuo and the aqueous layer was acidified to pH 1 using (HCl, 1N). Theaqueous layer was extracted with EtOAc and the combined organic extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo toafford2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)aceticacid (40 mg, 64% yield).

Step C: To a solution of2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)aceticacid (0.04 g, 0.105 mmol) in DMA (0.5 mL) was added propan-2-amine(0.0249 g, 0.422 mmol) and Hunig's Base (0.0184 mL, 0.105 mmol) followedby 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide(0.134 g, 0.211 mmol), and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was purified by reversephase chromatography (C18, 0-60% CH₃CN/water) to affordN-isopropyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)acetamide(0.0198 g, 0.0471 mmol, 44.7% yield). Mass spectrum (apci) m/z=421.2(M+H). ¹H NMR (CDCl₃) δ 8.49 (d, J=0.8 Hz, 1H), 8.27 (s, 1H), 8.25 (s,1H), 8.09 (s, 1H), 8.08 (s, 1H), 8.06 (d, J=2.5 Hz, 1H), 7.00 (dd,J=2.5, 0.8 Hz, 1H), 6.14 (d, J=7.4 Hz, 1H), 4.85 (s, 2H), 4.13-4.00 (m,2H), 2.07-1.86 (m, 4H), 1.13 (d, J=6.7 Hz, 3H), 0.86 (t, J=7.4 Hz, 6H).

Example 981-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol

To5-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)oxazolidin-2-one(0.04 g, 0.10 mmol) was added a mixture of 1:1 dioxanes/1M LiOH and thereaction mixture was stirred at 70° C. for 4 hours. The reaction mixturewas concentrated in vacuo and the material purified by reverse phasechromatography (C18, 5-75% CH₃CN/water) to afford1-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol(0.005 g, 0.01 mmol, 13% yield). Mass spectrum (apci) m/z=395.3 (M+H).¹H NMR (CDCl₃) δ 8.45 (d, J=0.8 Hz, 1H), 8.25 (s, 1H), 8.17 (s, 1H),8.06 (s, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.97 (s, 1H), 6.94 (dd, J=2.3, 1.0Hz, 1H), 4.32 (dd, J=13.9, 3.7 Hz, 1H), 4.23 (dd, J=13.9, 6.7 Hz, 1H),4.02 (m, 2H), 2.89 (dd, J=12.7, 4.1 Hz, 1H), 2.72 (dd, J=12.7, 7.0 Hz,1H), 2.06-1.85 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).

Example 99(R)-1-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol

Step A:4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(300 mg, 0.933 mmol), (S)-2-(chloromethyl)oxirane (864 mg, 9.3 mmol) andCs₂CO₃ (912 mg, 2.80 mmol) were placed in DMF (2 mL) and stirred for 3hours. Water was added and the reaction mixture was extracted withEtOAc. The combined organic layers were washed with water. The organiclayer was concentrated to give crude(S)-6-(1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinewhich was used in the next step without further purification.

Step B:(R)-6-(1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(30 mg, 0.0795 mmol) was placed in THF (1 mL). 2.0M Dimethylamine (397μL, 0.795 mmol) was added and the reaction vessel was sealed and heatedto 50° C. for 18 hours. The reaction mixture was concentrated and theresidue was purified over silica gel (2-20% MeOH in CH₂Cl₂) to afford(R)-1-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol(18.1 mg, 0.0428 mmol, 53.9% yield). Mass spectrum (apci) m/z=423.3(M+H). ¹H NMR (d₆-DMSO) δ 8.99 (d, J=0.8 Hz, 1H), 8.73 (s, 1H), 8.38 (s,1H), 8.34 (s, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.15 (s, 1H), 7.36 (dd,J=2.5, 1.0 Hz, 1H), 4.96 (m, 1H), 4.27 (dd, J=13.1, 2.9 Hz, 1H), 4.14(m, 1H), 4.08-3.95 (m, 2H), 2.28 (t, J=5.7 Hz, 2H), 2.21 (s, 6H),1.97-1.80 (m, 4H), 0.75 (t, J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 99.

Example Structure Name Data 100

(R)-1-(methylamino)-3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Massspectrum (apci) m/z = 409.2 (M + H) 101

(S)-1-(dimethylamino)-3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Massspectrum (apci) m/z = 423.3 (M + H) 102

(S)-1-(methylamino)-3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Massspectrum (apci) m/z = 409.2 (M + H) 103

(R)-1-(3- methoxyazetidin-1-yl)-3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Massspectrum (apci) m/z = 465.3 (M + H) 104

(S)-1-(3- methoxyazetidin-1-yl)-3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Massspectrum (apci) m/z = 465.3 (M + H) 105

(R)-1-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)-3- (pyrrolidin-1-yl)propan- 2-ol Massspectrum (apci) m/z = 449.3 (M + H) 106

(S)-1-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)-3- (pyrrolidin-1-yl)propan- 2-ol Massspectrum (apci) m/z = 449.3 (M + H)

Example 107(R)-1-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol

4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(40 mg, 0.124 mmol) was dissolved in DMF (0.5 mL) and 60% sodium hydride(5.97 mg, 0.149 mmol) was added, followed by(R)-2-(methoxymethyl)oxirane (14.5 μL, 0.162 mmol). The reaction mixturewas heated to 50° C. overnight. The reaction was cooled to ambienttemperature, diluted with water (3 mL) and extracted with EtOAc. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified over silica gel (2% MeOH in EtOAc) to afford(R)-1-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol(29.5 mg, 0.0720 mmol, 57.9% yield). Mass spectrum (apci) m/z=410.2(M+H). ¹H NMR (CDCl₃) δ 8.45 (m, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 8.03(m, 2H), 7.99 (s, 1H), 6.95 (dd, J=2.5, 1.0 Hz, 1H), 4.37 (dd, J=13.5,3.1 Hz, 1H), 4.31-4.20 (m, 2H), 4.03 (m, 1H), 3.45-3.55 (m, 5H),2.06-1.85 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 107.

Example Structure Name Data 108

(S)-1-methoxy-3-(4-(4- (1-(pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Mass spectrum (apci) m/z =410.2 (M + H) 109

(R)-1-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Mass spectrum (apci) m/z =380.2 (M + H) 110

(S)-1-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-2-ol Mass spectrum (apci) m/z =380.2 (M + H) 111

4,4,4-trifluoro-1-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =448.2 (M + H) 112

3,3-dimethyl-1-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =422.3 (M + H) 113

3-methyl-1-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =408.3 (M + H) 114

(S)-1-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =394.2 (M + H) 115

(R)-1-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =394.2 (M + H) 116

4-((4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)methyl)tetrahydro-2H- pyran-4-ol Massspectrum (apci) m/z = 436.2 (M + H)

Example 1172-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol

To a slurry of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.050 g, 0.16 mmol) in DMF (0.5 mL) was added CS₂CO₃ (0.10 g, 0.31mmol) and 2,2-dimethyloxirane (0.022 g, 0.31 mmol) and the reactionmixture was heated to 70° C. overnight. The reaction mixture waspartitioned between EtOAc and water. The combined organic phases wereseparated and washed with brine, dried over MgSO₄ and concentrated invacuo. The material was purified over silica gel (0-10% MeOH/CH₂Cl₂) toafford2-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol(0.011 g, 0.028 mmol, 18% yield). Mass spectrum (apci) m/z=394.2 (M+H).¹H NMR (CDCl₃) δ 8.47 (d J=1.0 Hz, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.04(d, J=2.5 Hz, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 6.96 (dd, J=2.5, 1.0 Hz,1H), 4.16 (s, 2H), 4.03 (m, 1H), 2.05-1.85 (m, 4H), 1.24 (s, 6H), 0.86(t, J=7.4 Hz, 6H).

Example 118trans-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.100 g, 0.311 mmol) and 1,4-dioxaspiro[4.5]dec-8-yl4-methylbenzenesulfonate (0.194 g, 0.622 mmol) in DMF (1.56 mL, 0.311mmol) was added Cs₂CO₃ (0.203 g, 0.622 mmol) and the mixture was stirredat 80° C. for 6 hours. The reaction mixture was cooled to ambienttemperature and then diluted with water (15 mL) and stirred for 10minutes. The reaction mixture was extracted with EtOAc and the combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified over silica gel (70%EtOAc/hexanes) to afford6-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(120 mg, 83% yield) as a white foam.

Step B: A solution of6-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.114 g, 0.247 mmol) in acetone (1.23 mL, 0.247 mmol) and HCl (0.823mL, 2.47 mmol, 3.0 M) was stirred at ambient temperature for 4 hours.The reaction mixture was treated with 3N NaOH (0.8 mL) and diluted withEtOAc (10 mL) and the layers were separated. The reaction mixture wasextracted with EtOAc and the combined organic extracts were dried overNa₂SO₄, filtered and concentrated. The residue was purified over silicagel (70% EtOAc/hexanes) to afford4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanone(94 mg, 91% yield) as a white foam.

Step C: A round bottom flask equipped with a stir bar and nitrogen inletwas charged with4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanone(0.090 g, 0.22 mmol) and MeOH (2.2 mL, 0.22 mmol). The reaction mixturewas chilled to 0° C. and NaBH₄ (0.016 g, 0.43 mmol) was added in oneportion. The reaction mixture was allowed to warm to room temperatureover 1.5 hours. The reaction mixture was diluted with a saturatedaqueous ammonium chloride solution, and extracted with EtOAc. Thecombined extracts were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified over silica gel (5% MeOH/CH₂Cl₂) to affordtrans-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanol(38 mg, 42% yield) as a white foam. Mass spectrum (apci) m/z=420.2(M+H). ¹H NMR (CDCl₃) δ 8.45 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 8.03(s, J=1.7 Hz, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 6.95 (m, 1H), 4.21 (tt,J=11.5, 3.7 Hz, 1H), 4.03 (m, 1H), 3.79 (m, 1H), 2.27 (m, 2H), 2.17 (m,2H), 2.06-1.85 (m, 6H), 1.54 (m, 2H), 0.86 (t, J=7.4 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 118.

Example Structure Name Data 119

cis-3-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)cyclobutanol Mass spectrum (apci) m/z =392.2 (M + H) 120

(1s,3s)-3-((4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)methyl)cyclobutanol Mass spectrum(apci) m/z = 406.2 (M + H)

Example 121cis-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanol

To a vial containingtrans-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanol(0.028 g, 0.0667 mmol) was added THF (1 mL). 2-Chloroacetic acid(0.00946 g, 0.100 mmol) was added followed by PPh₃ (0.0263 g, 0.100mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate(0.0158 mL, 0.100 mmol) was added as a THF solution (0.5 mL). Thesolution was protected from light and stirred for 4 hours as it slowlywarmed to ambient temperature. The THF was then removed in vacuo andreplaced with EtOAc. The solution was washed with a saturated aqueousNaHCO₃ solution, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was dissolved in dioxane (1 mL) and water was added (1 mL). A 1NNaOH solution was added until the pH reached >10 (0.5 mL). The mixturewas stirred for 1 hour and the reaction mixture was quenched with 1NKHSO₄ (1 mL). The reaction mixture was extracted with EtOAc. Thecombined organic phases were washed with a saturated aqueous NaHCO₃solution, dried over Na₂CO₃, filtered and concentrated. The residue waspurified over silica gel (40% acetone/hexanes), followed by a secondpurification by silica gel chromatography (5% MeOH/CH₂Cl₂) to affordcis-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanol(10.5 mg, 35% yield) as an off-white solid. Mass spectrum (apci)m/z=420.2 (M+H). ¹H NMR (CDCl₃) δ 8.46 (s, 1H), 8.27 (s, 1H), 8.19 (s,1H), 8.07 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.95 (s, 1H), 6.95 (dd,J=2.5, 1.0 Hz, 1H), 4.25 (tt, J=11.1, 3.7 Hz, 1H), 4.14 (m, 1H), 4.04(m, 1H), 2.28 (qd, J=12.9, 3.7 Hz, 2H), 2.09-1.85 (m, 8H), 1.75 (tt,J=13.7, 3.5 Hz, 2H), 0.86 (t, J=7.2 Hz, 6H).

Examples 122 and 123((1s,3s)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutyl)methanoland((1r,3r)-3-((4-(4-(1-(pentan-3-yl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutyl)methanol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.100 g, 0.311 mmol) and benzyl3-((tosyloxy)methyl)cyclobutanecarboxylate (0.233 g, 0.622 mmol) in DMF(1.56 mL, 0.311 mmol) was added cesium carbonate (0.203 g, 0.622 mmol)and the mixture was stirred at 80° C. for 20 hours. The reaction mixturewas diluted with water (15 mL) and stirred for 10 minutes. The mixturewas extracted with EtOAc and the combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified over silica gel (50% EtOAc/hexanes) to afford benzyl3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutanecarboxylate(138 mg, 84.7% yield) as a pale orange oil.

Step B: To a solution of benzyl3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutanecarboxylate(0.075 g, 0.14 mmol) in THF (1.4 mL, 0.14 mmol) at 0° C. was addeddiisobutylaluminum hydride (0.46 mL, 0.46 mmol) (1.0 M Hexanes). Thereaction mixture was stirred for 1 hour and then quenched with saturatedaqueous Na/K tartrate solution. The reaction mixture was stirred and thelayers were separated. The aqueous phase was extracted with EtOAc. Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified over silica gel (5% MeOH/CH₂Cl₂)to afford(3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutyl)methanol(53 mg, 88% yield) as a mixture of the (1s,3s) and (1r, 3r)diastereomers as a white foam.

Step C: The two diastereomers prepared in Step B were separated by aChiral Tech IA column (4.6 mm×250 mm, 5 micron) eluting with 20% EtOH inhexanes at 1 mL/min. Peak A (cis conformation (1s, 3s)): retentiontime=15.5 min; Mass spectrum (apci) m/z=420.2 (M+H); ¹H NMR (CDCl₃) δ8.47 (s, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.97(br s, 2H), 6.97 (m, 1H), 4.20 (d, J=7.1 Hz, 2H), 4.06 (tt, J=9.5, 4.7Hz, 1H), 3.59 (d, J=5.9 Hz, 2H), 2.83 (m, 1H), 2.47 (m, 1H), 2.22 (m,2H), 1.93 (m, 4H), 1.68 (m, 2H), 0.88 (t, J=7.7 Hz, 6H). Peak B (transconformation (1r, 3r)); retention time=18.1 min; Mass spectrum (apci)m/z=420.2 (M+H). ¹H NMR (CDCl₃) δ 8.47 (s, 1H), 8.29 (s, 1H), 8.19 (s,1H), 8.05 (d, J=2.4 Hz, 1H), 7.96 (br s, 2H), 6.97 (m, 1H), 4.29 (d,J=7.1 Hz, 2H), 4.06 (tt, J=9.5, 4.7 9.5 Hz, 1H), 3.71 (d, J=7.1 Hz, 2H),2.93 (m, 1H), 2.56 (m, 1H), 2.02 (m, 8H), 0.88 (t, J=7.7 Hz, 6H).

Example 1242-methyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol

Step A: To a stirred solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(64 mg, 0.1991 mmol) in 600 μL of DMF at room temperature in a cappedreaction vial was added ethyl 2-bromo-2-methylpropanoate (32.15 μL,0.2191 mmol), followed by Cs₂CO₃ (35.85 mg, 0.5974 mmol). The reactionmixture was capped and heated to 100° C. After 18 hours, another 3equivalents of cesium carbonate and 1.1 equivalents of ethyl2-bromo-2-methylpropanoate were added and the reaction was again heatedat 100° C. overnight. The reaction mixture was partitioned between ethylacetate (15 mL) and water (15 mL). The combined organic phases wereisolated and washed with water and brine. The combined organic phaseswere dried over MgSO₄, filtered and concentrated. The residue waspurified over silica gel (10 to 50% EtOAc in hexanes) to afford ethyl2-methyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propanoate(51 mg, 58% yield).

Step B: To a stirred solution of ethyl2-methyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propanoate(51 mg, 0.12 mmol) in 500 μL of anhydrous methanol at room temperatureunder nitrogen was added NaBH₄ (8.1 mg, 0.35 mmol) as a solid. After 1hour, another 3 equivalents of sodium borohydride was added. Thereaction mixture was quenched with 1 mL of saturated ammonium chloridesolution and stirred for 5 minutes. The clear solution was diluted with15 mL of ethyl acetate and shaken. The organic layer was isolated,washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified over silica gel (20-80% EtOAc in hexanes) to afford2-methyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol(28 mg, 55% yield) as a white foam. Mass spectrum (apci) m/z=394.2(M+H). ¹H NMR (CDCl₃) δ 8.45 (d, J=1.0 Hz, 1H), 8.27 (s, 1H), 8.18 (s,1H), 8.10 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.95 (s, 1H), 6.95 (dd,J=2.5, 1.0 Hz, 1H), 4.02 (m, 1H), 3.86 (m, 2H), 3.76 (m, 1H), 2.06-1.85(m, 4H), 1.63 (s, 6H), 0.85 (t, J=7.4 Hz, 6H).

Example 125(S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol

Step A: To a slurry of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.05 g, 0.2 mmol) in DMF (0.5 mL) was added(S)-tert-butyl(2-chloropropoxy)dimethylsilane (0.06 g, 0.3 mmol) andCs₂CO₃ (0.1 g, 0.3 mmol) and the reaction mixture was heated to 70° C.overnight. The reaction mixture was partitioned between EtOAc and water.The combined organic phases were separated and washed with brine, driedover MgSO₄ and concentrated in vacuo. The residue was purified oversilica gel (0-100% EtOAc/CH₂Cl₂) to afford(S)-6-(1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.05 g, 0.1 mmol, 65% yield).

Step B: To(S)-6-(1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.05 g, 0.1 mmol) was added HCl in isopropyl alcohol (5 M, 2 mL) andthe reaction mixture was heated to 80° C. overnight. The reactionmixture was concentrated in vacuo. The resulting material waspartitioned between EtOAc and 1N NaOH. The combined organic phases werewashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified over silica gel (0-10% MeOH/CH₂Cl₂) to afford(S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol(0.022 g, 0.058 mmol, 69% yield). Mass spectrum (apci) m/z=380.2 (M+H).¹H NMR (CDCl₃) δ 8.44 (d, J=0.8 Hz, 1H), 8.25 (s, 1H), 8.18 (s, 1H),8.02 (m, 2H), 7.98 (s, 1H), 6.94 (dd, J=2.5, 1.0 Hz, 1H), 4.32-4.22 (m,2H), 4.11-3.94 (m, 2H), 2.06-1.85 (m, 4H), 1.28 (d, J=6.3 Hz, 3H), 0.86(t, J=7.4 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 125.

Example Structure Name Data 126

(S)-2-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-1-ol Mass spectrum (apci) m/z =380.2 (M + H)

Example 127(S)-2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholinetrifluoroacetic acid

4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(40 mg, 0.124 mmol), Cs₂CO₃ (122 mg, 0.373 mmol) and (S)-tert-butyl2-(bromomethyl)morpholine-4-carboxylate (349 mg, 1.24 mmol) were placedin DMF (1 mL) and the reaction mixture was stirred for 24 hours. Waterwas added and the reaction mixture was extracted with EtOAc. The organiclayer was concentrated and the residue was taken up in 10% MeOH inCH₂Cl₂. 4 N HCl (2 mL) was added and the reaction mixture was stirredfor 1 hour. The reaction mixture was concentrated and the residue waspurified by reverse phase chromatography (0-60% ACN:water with 0.1% TFA)to provide(S)-2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine(10.2 mg, 0.0243 mmol, 19.5% yield). ¹H NMR (CDCl₃) δ 10.5 (br s, 1H),9.85 (br s, 1H), 8.49 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.05 (d,J=2.5 Hz, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 6.97 (dd, J=2.5, 0.8 Hz, 1H),4.85 (br s, 2H), 4.36 (m, 2H), 4.24 (m, 1H), 4.10-3.90 (m, 3H), 3.40 (d,J=12.1 Hz, 1H), 3.21 (d, J=12.1 Hz, 1H), 3.03 (m, 1H), 2.82 (t, J=12.3Hz, 1H), 2.04-1.84 (m, 4H), 0.84 (t, J=7.2 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 127.

Example Structure Name Data 128

(R)-2-((4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)methyl)morpholine Mass spectrum (apci)m/z = 412.3 (M + H)

Example 129(S)-2-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.100 g, 0.311 mmol) and (R)-tert-butyl2,2-dimethyl-4-((tosyloxy)methyl)oxazolidine-3-carboxylate (0.240 g,0.622 mmol) in DMF (1.56 mL, 0.311 mmol) was added Cs₂CO₃ (0.203 g,0.622 mmol) and the mixture was stirred at 80° C. for 16 hours. Thereaction mixture was cooled to ambient temperature, diluted with water(15 mL) and stirred for 10 minutes. The reaction mixture was extractedwith EtOAc and the combined organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedover silica gel (50% EtOAc/hexanes) to afford (S)-tert-butyl2,2-dimethyl-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)oxazolidine-3-carboxylate(158 mg, 95% yield) as a thick colorless foaming oil.

Step B: A solution of (S)-tert-butyl2,2-dimethyl-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)oxazolidine-3-carboxylate(0.148 g, 0.277 mmol) in acetone (1.38 mL, 0.277 mmol) and HCl (1.85 mL,5.54 mmol, 3.0 M) was stirred at ambient temperature for 5 hours. Thereaction mixture was treated with 3N NaOH (1.8 mL) and saturated aqueousNaHCO₃ and then diluted with EtOAc (10 mL) and the layers wereseparated. The aqueous layer was extracted with EtOAc and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated. Thecrude(S)-2-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol(91 mg, 83% yield) was used directly in the next step.

Step C: To a solution of(S)-2-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol(0.043 g, 0.1090 mmol) in dichloroethane (1.5 mL) was added formaldehyde(0.041 mL, 0.55 mmol) (37% aqueous). After stirring for 15 minutes thereaction mixture was treated with NaBH(OAc)₃ (0.115 g, 0.545 mmol) andthe mixture was stirred for 2 hours at ambient temperature. The reactionmixture was diluted with water and the reaction mixture was extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄, filteredand concentrated. The residue was purified over silica gel (10%MeOH/CH₂Cl₂) to afford(S)-2-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol(22 mg, 47% yield). Mass spectrum (apci) m/z=423.3 (M+H). ¹H NMR (CDCl₃)δ 8.46 (d, J=0.8 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 8.03 (d, J=2.5 Hz,1H), 7.98 (s, 1H), 7.97 (s, 1H), 6.95 (dd, J=2.5, 1.0 Hz, 1H), 4.42 (dd,J=13.9, 5.7 Hz, 1H), 4.15 (dd, J=13.9, 7.8 Hz, 1H), 4.03 (m, 1H), 3.58(dd, J=11.2, 4.9 Hz, 1H), 3.47 (dd, J=11.2, 8.2 Hz, 1H), 3.19 (m, 1H),2.41 (s, 6H), 2.07-1.85 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 129.

Example Structure Name Data 130

(R)-2-amino-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-1-ol Mass spectrum (apci) m/z =395.2 (M + H) 131

(R)-2-(dimethylamino)-3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-1-ol Massspectrum (apci) m/z = 423.2 (M + H)

Examples 132 and 133(1R,2S,4s)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-dioland(1R,2S,4r)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-diol

Step A: To a stirred solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(139 mg, 0.433 mmol) in 1.5 mL of DMF at room temperature under nitrogenwas added Cs₂CO₃ (51.9 mg, 0.865 mmol), followed by cyclopent-3-en-1-ylmethanesulfonate (140 mg, 0.865 mmol). The reaction mixture was heatedto 80° C. overnight. An additional 2 equivalents of cesium carbonate andcyclopent-3-en-1-yl methanesulfonate were added and the reaction mixturewas heated overnight. The reaction mixture was cooled to roomtemperature and diluted to 30 mL with ethyl acetate. The organic layerwas washed with water and brine. The combined organic phases were driedover MgSO₄, filtered and concentrated. The residue was purified oversilica gel (20-80% EtOAc in hexanes) to afford6-(1-(cyclopent-3-en-1-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(42 mg, 25% yield).

Step B: To a stirred solution of6-(1-(cyclopent-3-en-1-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(42 mg, 0.108 mmol) in 1 mL of 8:1 acetone:water at room temperatureunder nitrogen was added N-methylmorpholine-N-oxide (22.9 mg, 0.195mmol) neat as a solid followed by OsO₄ (42.5 μL, 0.00542 mmol) (4% watersolution) by syringe and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with 0.2 Maqueous Na₂S₂O₃ (1 mL) and stirred for 5 minutes. The reaction mixturewas diluted with 15 mL of dichloromethane and washed with 0.2 M sodiumthiosulfate. The combined organic phases were isolated, dried overMgSO₄, filtered and concentrated to a brown oil that was purified oversilica gel (0-10% MeOH in dichloromethane) to afford two diastereomers.The faster eluting fraction (Peak A) was(1R,2S,4r)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-diol(minor isomer): Mass spectrum (apci) m/z=422.2 (M+H). ¹H NMR (CDCl₃) δ8.44 (d, J=0.8 Hz, 1H), 8.26 (s, H), 8.15 (s, 1H), 8.04 (d, J=2.3 Hz,1H), 8.00 (s, 2H), 6.96 (dd, J=2.3, 1.0 Hz, 1H), 4.79 (tt, J=9.4, 3.3Hz, 1H), 4.46 (m, 1H), 4.12 (m, 1H), 4.03 (m, 1H), 2.56 (m, 2H), 2.11(m, 2H), 2.05-1.85 (m, 4H), 0.86 (t, J=7.4 Hz, 6H). The slower elutingfraction (Peak B) was(1R,2S,4s)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-diol(major isomer): Mass spectrum (apci) m/z=422.2 (M+H). ¹H NMR (CDCl₃) δ8.45 (d, J=0.8 Hz, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.03 (d, J=2.5 Hz,1H), 7.98 (s, 1H), 7.95 (s, 1H), 6.95 (dd, J=2.3, 0.8 Hz, 1H), 5.05 (m,1H), 4.51 (m, 2H), 4.03 (m, 1H), 3.72 (m, 1H), 2.44-2.35 (m, 6H),2.05-1.85 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).

Example 134N-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)cyclopropanaminetrifluoroacetate

Step A:4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(450 mg, 1.40 mmol), Cs₂CO₃ (1369 mg, 4.20 mmol) and(2-bromoethoxy)(tert-butyl)dimethylsilane (670 mg, 2.80 mmol) wereplaced in DMF (8 mL) and stirred for 18 hours. Water was added and themixture was extracted with EtOAc. The combined organic extracts werewashed with water. The organic layer was concentrated and the crude6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(672 mg, 100% yield) was used in the next step without furtherpurification.

Step B:6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(672 mg, 1.40 mmol) was placed in 10% MeOH in CH₂Cl₂ (20 mL) and 4 N HClin dioxane (2 mL) as added. The reaction mixture was stirred for 45minutes. The reaction mixture was adjusted to pH 9 with slow addition ofsaturated NaHCO₃. The reaction mixture was extracted with CH₂Cl₂,combined and concentrated. The crude material was used in the next stepwithout further purification.

Step C:2-(4-(4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol(512 mg, 1.40 mmol) and Et₃N (391 μL, 2.80 mmol) were placed in THF (15mL). Methanesulfonyl chloride (136 μL, 1.75 mmol) was added and thereaction mixture was stirred for 1 hour. Water was added and the mixturewas extracted with CH₂Cl₂. The combined organic layers wereconcentrated. The residue was purified over silica gel (1-10% MeOH inCH₂Cl₂) to provide2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethylmethanesulfonate (481 mg, 1.08 mmol, 77.4% yield).

Step D:2-(4-(4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethylmethanesulfonate (40 mg, 0.0902 mmol), Cs₂CO₃ (88.2 mg, 0.271 mmol) andcyclopropanamine (15.4 mg, 0.271 mmol) were placed in DMF (1 mL) andstirred over the weekend. The reaction mixture was concentrated and thecrude material was purified by reverse phase chromatography (0-50%CH₃CN/water w/0.1% TFA) to provideN-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)cyclopropanaminetrifluoroacetate (20.7 mg, 0.0512 mmol, 56.7% yield)t. Mass spectrum(apci) m/z=405.3 (M+H). ¹H NMR (CDCl₃) δ 8.48 (s, 1H), 8.34 (s, 1H),8.29 (s, 1H), 8.13 (s, 1H), 8.11 (d, J=2.5 Hz, 1H), 7.94 (s, 1H), 7.10(m, 1H), 4.61 (m, 2H), 4.06 (m, 1H), 3.73 (m, 2H), 2.70 (m, 1H),2.05-1.86 (m, 4H), 1.15 (m, 2H), 0.90 (m, 2H), 0.85 (t, J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 134.

Example Structure Name Data 135

4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazine Massspectrum (apci) m/z = 419.3 (M + H) 136

(R)-6-(1-(2-(3- methoxypyrrolidin-1- yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazine Mass spectrum(apci) m/z = 449.3 (M + H) 137

(S)-6-(1-(2-(3- methoxypyrrolidin-1- yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazine Mass spectrum(apci) m/z = 449.3 (M + H) 138

6-(1-(2-(3-fluoroazetidin-1- yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazine Mass spectrum(apci) m/z = 423.2 (M + H) 139

1-(2-(4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)ethyl)piperidin-4-ol Mass spectrum (apci) m/z =449.3 (M + H) 140

(R)-1-(2-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1- yl)ethyl)pyrrolidin-3-olMass spectrum (apci) m/z = 435.2 (M + H) 141

(S)-1-(2-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1- yl)ethyl)pyrrolidin-3-olMass spectrum (apci) m/z = 435.2 (M + H) 142

(S)-1-methyl-3-((2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)ethyl)amino)pyrrolidin-2- one Mass spectrum (apci) m/z = 462.2 (M +H) 143

(R)-1-methyl-3-((2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)ethyl)amino)pyrrolidin-2- one Mass spectrum (apci) m/z = 462.3 (M +H) 144

4-(2-(4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)ethyl)piperazin-2-one Mass spectrum (apci) m/z =448.2 (M + H) 145

(3-((2-(4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- yl)-1H-pyrazol-1-yl)ethyl)amino)cyclobutyl) methanol Mass spectrum (apci) m/z = 449.3(M + H) 146

(1-(2-(4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)ethyl)piperidin-4- yl)methanol Mass spectrum (apci)m/z = 463.3 (M + H)

Example 1471-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)piperazin-2-one

tert-Butyl 3-oxopiperazine-1-carboxylate (0.135 g, 0.676 mmol) was addedto a solution of sodium hydride (0.0271 g, 0.676 mmol) in DMF (2.25 mL,0.225 mmol).2-(4-(4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethylmethanesulfonate (0.100 g, 0.225 mmol) was slowly added and the reactionmixture was stirred at room temperature for 23 hours. Water (15 mL) wasslowly added and the reaction mixture was extracted with EtOAc. Thecombined organic extracts were dried over Na₂SO₄ and concentrated. Theresidue was purified over silica gel (0-10% MeOH in CH₂Cl₂). Theconcentrated material was dissolved in 10% MeOH in CH₂Cl₂ and 6 N HCl inisopropyl alcohol (3 mL) was added and the reaction mixture was stirredfor 2 hours and concentrated. The resulting solid was purified oversilica gel (0-10% MeOH w/NH₄OH in CH₂Cl₂) to afford1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)piperazin-2-one(16.1 mg, 0.0360 mmol, 16.0% yield) as a white foam. Mass spectrum(apci) m/z=448.2 (M+H). ¹H NMR (CDCl₃) δ 8.43 (d, J=1.0 Hz, 1H), 8.26(s, 1H), 8.18 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 7.94 (s,1H), 6.96 (dd, J=2.5, 1.0 Hz, 1H), 4.39 (t, J=6.1 Hz, 2H), 4.03 (m, 1H),3.75 (t, J=5.9 Hz, 2H), 3.15 (s, 2H), 2.88 (m, 1H), 2.84 (m, 2H), 2.52(m, 2H), 2.05-1.85 (m, 4H), 0.85 (t, J=7.4 Hz, 6H).

Example 148(R)-2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-amine

Step A:4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(125 mg, 0.389 mmol), 2-(3-bromo-2-methoxypropyl)isoindoline-1,3-dione(145 mg, 0.49 mmol) and Cs₂CO₃ (380 mg, 1.17 mmol) were heated in DMF (8mL) to 50° C. for 18 hours. The reaction mixture was cooled and waterwas added. The reaction mixture was extracted with EtOAc. The combinedorganic layers were washed with water. The organic layer wasconcentrated and purified over silica gel (0-5% MeOH in CH₂Cl₂) toafford2-(2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propyl)isoindoline-1,3-dione(60 mg, 0.111 mmol, 28.6% yield) as a racemic mixture. The racemicmaterial was purified by chiral chromatography to afford 2 peaks thatwere arbitrarily assigned absolute configuration. Peak A: Arbitrarilyassigned the R configuration. Peak B: Arbitrarily assigned the Sconfiguration.

Step B:(R)-2-(2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propyl)isoindoline-1,3-dione(26 mg, 0.048 mmol) [Peak A from previous step] was placed in THF (2mL). Hydrazine monohydrate (6.0 mg, 0.12 mmol) was added and thereaction mixture was heated to 65° C. for 18 hours. The reaction mixturewas cooled and water was added. The reaction mixture was extracted withCH₂Cl₂ and the combined organic extracts were concentrated. The residuewas purified over silica gel (0.5-18% MeOH w/NH₄OH in CH₂Cl₂) to afford(R)-2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-amine(isolated “Peak A”) (6.7 mg, 0.016 mmol, 34% yield). Mass spectrum(apci) m/z=409.2 (M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=0.8 Hz, 1H), 8.27(s, 1H), 8.17 (s, 1H), 8.03 (m, 2H), 7.99 (s, 1H), 6.95 (dd, J=2.3, 0.8Hz, 1H), 4.36 (dd, J=14.1, 5.1 Hz, 1H), 4.31 (dd, J=14.1, 6.1 Hz, 1H),4.03 (m, 1H), 3.69 (pentet, 1H), 3.38 (s, 3H), 2.92 (dd, J=13.3, 4.5 Hz,1H), 2.75 (dd, J=13.3, 5.5 Hz, 1H), 2.09-1.85 (m, 6H), 0.86 (t, J=7.4Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 148.

Example Structure Name Data 149

(S)-2-methoxy-3-(4-(4- (1-(pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propan-1- amine Mass spectrum (apci)m/z = 409.2 (M + H)

Example 1502-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol

Step A:4-Chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (1.2 g, 3.2 mmol),1-(trans-2-methylcyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.1 g, 3.8 mmol) and K₂CO₃ (3.2 mL, 6.3 mmol) were dissolved in THF (20mL) and nitrogen bubbled through the reaction mixture for 3 minutes.XPHOS (0.15 g, 0.32 mmol) and Pd₂(dba)₃ (0.072 g, 0.079 mmol) were addedand the reaction mixture was heated to 60° C. overnight. The reactionmixture was cooled to room temperature, partitioned between water andEtOAc, dried over sodium sulfate, filtered and concentrated. The residuewas purified over silica gel (50-75% EtOAc in hexanes) to afford6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(trans-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(1.3 g, 2.8 mmol, 88% yield) as an oil.

Step B:6-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(trans-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(1.3 g, 2.78 mmol) was dissolved in TFA (25 mL) and heated to 80° C. for2.5 hours. The reaction mixture was concentrated and partitioned betweenEtOAc and 1M NaOH, dried over sodium sulfate, filtered and concentrated.The residue was purified over silica gel (90% EtOAc in hexanes) toafford a racemic mixture of4-(1-(trans-2-methylcyclohexyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(630 mg, 1.81 mmol, 65.2% yield) as a pale yellow solid.

Step C: The racemic material (630 mg) prepared in Step B was purified bychiral chromatography (Chiral Tech OJ-H, 22 mm×250 mm, 5 micron, 25%EtOH in hexanes, 23 mL/min) to afford two peaks that were arbitrarilyassigned absolute chirality: Peak A (retention time=8.9 min):4-(1-((1S,2S)-2-methylcyclohexyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(287 mg, 0.826 mmol, 29.7% yield) and Peak B (retention time=11.3 min):4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(263 mg, 0.757 mmol, 27.2% yield).

Step D:4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(80 mg, 0.23 mmol) was dissolved in DMF (1 mL) andcis-2-phenyl-1,3-dioxan-5-yl methanesulfonate (119 mg, 0.46 mmol) andCs₂CO₃ (225 mg, 0.69 mmol) were added and heated to 80° C. overnight.The reaction mixture was diluted with water (3 mL) and partitionedbetween water and EtOAc, dried over sodium sulfate, filtered andconcentrated. The residue was purified over silica gel to afford4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)-6-(1-(cis-2-phenyl-1,3-dioxan-5-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(68 mg, 0.13 mmol, 58% yield).

Step E:4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)-6-(1-((2R,5r)-2-phenyl-1,3-dioxan-5-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(68 mg, 0.13 mmol) was suspended in EtOH (1 mL) and hydrogen chloride(56 μL, 0.67 mmol) was added and the reaction heated to 60° C. for 4hours. The reaction mixture was partitioned between 1N NaOH and CH₂Cl₂,dried over sodium sulfate, filtered and concentrated. The residue waspurified over silica gel (6% MeOH in CH₂Cl₂) to afford2-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol(Peak A) (19 mg, 0.045 mmol, 34% yield) as a white solid. Mass spectrum(apci) m/z=422.2 (M+H). ¹H NMR (d₆-DMSO) δ 8.99 (m, 1H), 8.73 (s, 1H),8.37 (s, 2H), 8.15 (m, 2H), 7.35 (m, 1H), 4.93 (m, 2H), 4.30 (m, 1H),3.92 (td, J=11.0, 4.9 Hz, 1H), 3.79 (t, J=5.7 Hz, 4H), 2.10-1.67 (m,6H), 1.39 (m, 2H), 1.17 (m, 1H), 0.65 (d, J=6.5 Hz, 3H).

The following compounds were prepared according to the proceduredescribed for Example 150.

Example Structure Name Data 151

(R)-3-(4-(4-(1-((1R,2R)- 2-methylcyclohexyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Massspectrum (apci) m/z = 422.2 (M + H) 152

(S)-3-(4-(4-(1-((1R,2R)- 2-methylcyclohexyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Massspectrum (apci) m/z = 422.2 (M + H)

Example 153(1R,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol

Step A: To a stirred solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(105 mg, 0.327 mmol) in 1 mL of DMF at room temperature under nitrogenwas added NaH (14.4 mg, 0.359 mmol) (60% oil dispersion). After 10minutes, 6-oxabicyclo[3.1.0]hexane (31.1 μL, 0.359 mmol) was added bysyringe. After 3 hour, an additional 1 equivalent each of sodium hydrideand 6-oxabicyclo[3.1.0]hexane were added. The reaction mixture washeated to 65° C. overnight. The reaction mixture was cooled to roomtemperature and quenched with saturated ammonium chloride solution (1mL). The mixture was partitioned between ethyl acetate (15 mL) and water(15 mL). The combined organic phases were isolated and washed with waterand brine. The combined organic phases were dried over MgSO₄, filteredand concentrated to afford crudetrans-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanolwhich was used in the next step without purification.

Step B: To a stirred solution of crudetrans-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol(87 mg, 0.21 mmol) in 2.1 mL of dichloromethane at room temperatureunder nitrogen was added imidazole (15 mg, 0.21 mmol) followed bytert-butyldimethylsilyl chloride (32 mg, 0.21 mmol) and stirredovernight. The reaction mixture was then diluted to 15 mL withdichloromethane and washed with 10% citric acid solution and then withsaturated sodium bicarbonate. The combined organic phases were isolated,dried over MgSO₄, filtered and concentrated. The residue was purifiedover silica gel (10-50% EtOAc in hexanes). The purified racemic materialwas separated by chiral chromatography (Phenomenex Lux-2, 4.6 mm×250 mm,5 micron, 20% EtOH in hexanes, 1 mL/min) to provide 2 enantiomers, PeakA (4.8 min) Arbitrarily assigned as6-(1-((1R,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazineand Peak B (5.5 min). Arbitrarily assigned as6-(1-((1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

Step C: To a stirred solution of6-(1-((1R,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(19 mg, 0.037 mmol) [Peak A] in 1 mL of THF at room temperature undernitrogen was added tetrabutylammonium fluoride (73 μL, 0.073 mmol) (1Min THF) by syringe. After 45 minutes, the reaction mixture was completeand purified over silica gel (0-5% MeOH in CH₂Cl₂) to afford(1R,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol(Peak A) (14 mg, 94% yield). Mass spectrum (apci) m/z=406.2 (M+H). ¹HNMR (CDCl₃) δ 8.43 (d, J=0.8 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.02(d, J=2.3 Hz, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 6.94 (dd, J=2.5, 0.8 Hz,1H), 4.47 (qd, 7.6 1.6 Hz, 1H), 4.39 (m, 1H), 4.02 (m, 1H), 3.16 (d,J=2.2 Hz, 1H), 2.38 (m, 1H), 2.25-2.11 (m, 2H), 2.06-1.85 (m, 6H), 1.79(m, 1H), 0.85 (t, J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 153.

Example Structure Name Data 154

(1S,2S)-2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)cyclopentanol Mass spectrum (apci) m/z= 406.2 (M + H) 155

(2S,3S)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =394.2 (M + H) 156

(2R,3R)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =394.2 (M + H) 157

(2R,3S)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =394.2 (M + H) 158

(2S,3R)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butan-2-ol Mass spectrum (apci) m/z =394.2 (M + H) 159

(3S,4R)-4-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)tetrahydrofuran-3-ol Mass spectrum(apci) m/z = 408.2 (M + H) 160

(3R,4S)-4-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)tetrahydrofuran-3-ol Mass spectrum(apci) m/z = 408.2 (M + H)

Example 161trans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol

To a solution oftrans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutylpivalate (0.079 g, 0.17 mmol) in THF (1.1 mL, 0.17 mmol) at 0° C. wasadded diisobutylaluminum hydride (0.53 mL, 0.53 mmol) (1.0 M Hexanes).The reaction mixture was stirred for 1 hour and then carefully quenchedwith a saturated aqueous Na/K tartrate solution. The reaction mixturewas stirred and the layers were separated. The aqueous phase wasextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered and concentrated. The residue was purified over silicagel (EtOAc) to affordtrans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanolas a white foam. Mass spectrum (apci) m/z=392.2 (M+H). ¹H NMR (CDCl₃) δ8.45 (d, J=1.0 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 8.03 (d, J=2.5 Hz,1H), 8.01 (s, 1H), 7.99 (s, 1H), 6.95 (dd, J=2.3, 1.0 Hz, 1H), 5.05 (m,1H), 4.79 (m, 1H), 4.03 (m, 1H), 2.93 (m, 2H), 2.58 (m, 2H), 2.06-1.85(m, 5H), 0.86 (t, J=7.4 Hz, 6H).

Example 162(1s,3s)-1-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol

3-(4-(4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanone(25 mg, 0.0642 mmol) was placed in THF and cooled to 0° C.Methylmagnesium bromide (60.2 μL, 0.0963 mmol) was added and thereaction mixture was stirred at 0° C. for 15 minutes. Water was addedslowly and the reaction mixture was extracted with CH₂Cl₂. The organiclayers were combined and concentrated. The residue was purified oversilica gel (0-8% MeOH in CH₂Cl₂) and then by reverse phasechromatography (C18, 5-95% CH₃CN in water) to provide(1s,3s)-1-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol(23.8 mg, 0.0587 mmol, 91.4% yield). Mass spectrum (apci) m/z=406.2(M+H). ¹H NMR (CDCl₃) δ 8.45 (d, J=0.8 Hz, 1H), 8.26 (s, 1H), 8.17 (d,J=0.6 Hz, 1H), 8.03 (m, 2H), 8.00 (s, 1H), 6.95 (dd, J=2.5, 1.0 Hz, 1H),4.57 (m, 1H), 4.03 (m, 1H), 3.38 (s, 1H), 2.78 (m, 2H), 2.67 (m, 2H),2.07-1.86 (m, 4H), 1.48 (s, 3H), 0.86 (t, J=7.4 Hz, 6H).

Examples 163 and 164(1s,3s)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanoland(1r,3r)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol

Step A: Methyltriphenylphosphonium bromide (0.411 g, 1.15 mmol) andpotassium 2-methylpropan-2-olate (0.129 g, 1.15 mmol) were placed in THF(7.34 mL, 1.03 mmol) and the reaction mixture was stirred for 2 hours.3-(4-(4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanone(0.400 g, 1.03 mmol) was added and the reaction mixture was allowed tocontinue stirring for 2 hours. Water (20 mL) was added the reactionmixture was extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, and concentrated. The residue was purified over silica gel(0-8% MeOH in CH₂Cl₂), followed by reverse phase chromatography (C18,5-95% CH₃CN/Water) to afford6-(1-(3-methylenecyclobutyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.070 g, 0.181 mmol, 17.6% yield) as a white foam.

Step B: To a stirred solution of6-(1-(3-methylenecyclobutyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(58 mg, 0.150 mmol) in 1 mL of 8:1 acetone:water at room temperatureunder nitrogen was added N-methylmorpholine-N-oxide (31.6 mg, 0.269mmol) followed by OsO₄ (58.7 μL, 0.00748 mmol) (4% water solution). Thereaction mixture was stirred at room temperature for 1 hour, thenquenched with 0.2 M aqueous Na₂S₂O₃ (1 mL) and stirred for 5 minutes.The reaction mixture was diluted with 15 mL of dichloromethane andwashed mL with 0.2 M sodium thiosulfate. The combined organic phaseswere isolated, dried over MgSO₄, filtered and concentrated and purifiedover silica gel (0% to 10% MeOH in CH₂Cl₂) to afford 2 isomers. Fastereluting peak=Peak A:(1s,3s)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol(7.2 mg, 0.0171 mmol, 11.4% yield) Mass spectrum (apci) m/z=422.2 (M+H).¹H NMR (CDCl₃) δ 8.46 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 8.04 (s, H),8.03 (d, J=2.5 Hz, 1H), 8.02 (s, 1H), 6.95 (dd, J=2.5, 1.0 Hz, 1H), 4.58(m, 1H), 4.03 (m, 1H), 3.70 (m, 3H), 2.88 (m, 2H), 2.63 (m, 2H),2.08-1.86 (m, 5H), 0.86 (t, J=7.4 Hz, 6H); and a slower elutingpeak=Peak B:(1r,3r)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol(17.6 mg, 0.0418 mmol, 27.9% yield). Mass spectrum (apci) m/z=422.2(M+H). ¹H NMR (CDCl₃) δ 8.45 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 8.03(d, J=2.2 Hz, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 6.95 (d, J=2.2 Hz, 1H),5.08 (pentet, J=7.5 Hz, 1H), 4.03 (m, H), 3.77 (s, 2H), 2.79 (m, 2H),2.65 (m, 2H), 2.50 (br s, 1H), 2.12 (br s, 1H), 2.05-1.86 (m, 4H), 0.86(t, J=7.1 Hz, 6H).

Example 165(trans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.100 g, 0.311 mmol) and methyl 3-chlorocyclobutanecarboxylate (0.0925g, 0.622 mmol) in DMF (1.56 mL, 0.311 mmol) was added cesium carbonate(0.203 g, 0.622 mmol) and the reaction mixture was stirred at 80° C. for5 hours. The reaction mixture was cooled to ambient temperature, dilutedwith water (15 mL) and stirred for 10 minutes. The reaction mixture wasextracted with EtOAc and the combined extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedover silica gel (50% EtOAc/hexanes) to afford two isomers. Fastereluting peak: trans-methyl3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylate(28 mg, 21% yield) as an off-white foam. Slower eluting peak: cis-methyl3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylate(58 mg, 43% yield) as a thick oil.

Step B: To a solution of trans-methyl3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylate(0.025 g, 0.058 mmol) in THF (0.58 mL, 0.058 mmol) at 0° C. was addeddiisobutylaluminum hydride (0.18 mL, 0.18 mmol) (1.0 M Hexanes). Themixture was stirred for 1 hour and then quenched with saturated aqueousNa/K tartrate solution. The reaction mixture was stirred and the layerswere separated. The aqueous phase was extracted with EtOAc. The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified over silica gel (5% MeOH/CH₂Cl₂) to afford((1r,3r)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol(20 mg, 85% yield) as an off-white foam. Mass spectrum (apci) m/z=406.2(M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=0.8 Hz, 1H), 8.27 (s, 1H), 8.16 (s,1H), 8.03 (m, 2H), 7.99 (s, 1H), 6.95 (dd, J=2.5, 1.0 Hz, 1H), 4.95(pentet, J=7.6 Hz, 1H), 4.03 (m, 1H), 3.82 (m, 2H), 2.80 (m, 2H), 2.66(m, 1H), 2.46 (m, 2H), 2.05-1.85 (m, 4H), 0.86 (t, J=7.4 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 165.

Example Structure Name Data 166

(cis-3-(4-(4-(1-(pentan- 3-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)cyclobutyl)methanol Mass spectrum(apci) m/z = 406.2 (M + H)

Example 167(1r,3r)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide

To a vial was added (1r,3r)-methyl3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylate(0.049 g, 0.11 mmol) and 7 N NH₃ in methanol (0.81 mL, 5.7 mmol) and thevial was sealed with Teflon lined cap. The mixture was warmed to 60° C.and stirred for 40 hours. Additional 7 N NH₃ in methanol (0.81 mL, 5.7mmol) was added and the mixture was stirred at 80° C. for 48 hours. Themixture was cooled to ambient temperature and diluted with EtOAc. Themixture was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified over silica gel (5% MeOH/CH₂Cl₂)to afford(1r,3r)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide(21 mg, 44% yield) as an off-white solid. Mass spectrum (apci) m/z=449.2(M+H). ¹H NMR (CDCl₃) δ 8.46 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 8.03(d, J=2.5 Hz, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 6.95 (dd, J=2.4, 0.8 Hz,1H), 5.48 (br d, J=11.1 Hz, 2H), 5.15 (pentet, J=7.8 Hz, 1H), 4.03 (m,1H), 3.17 (m, 1H), 2.95 (m, 2H), 2.83 (m, 2H), 2.06-1.86 (m, 4H), 0.86(t, J=7.2 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 167.

Example Structure Name Data 168

(1s,3s)-3-(4-(4-(1-(pentan- 3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 6-yl)-1H-pyrazol-1- yl)cyclobutanecarboxamideMass spectrum (apci) m/z = 406.2 (M + H) 169

(1r,3r)-N,N-dimethyl-3-(4- (4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)cyclobutanecarboxamide Mass spectrum (apci) m/z = 447.3 (M + H) 170

(1s,3s)-N,N-dimethyl-3-(4- (4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)cyclobutanecarboxamide Mass spectrum (apci) m/z = 447.2 (M + H)

Example 171(1r,3r)-N-(2-hydroxyethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide

Step A: To a vial was added (1r,3r)-methyl3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylate(0.049 g, 0.113 mmol) and 2-(tetrahydro-pyran-2-yloxy)-ethylamine(0.0328 g, 0.226 mmol), followed by lithium bis(trimethylsilyl)amidesolution (0.170 mL, 0.170 mmol, 1.0M toluene). The reaction mixture wasstirred for 2 hours. Additional lithium bis(trimethylsilyl)amidesolution (0.170 mL, 0.170 mmol) was added. The reaction mixture wasstirred for another 2 hours and quenched by the addition of a saturatedaqueous NH₄Cl solution. The reaction mixture was ten extracted withEtOAc, and the combined extracts were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified over silica gel (4%MeOH/EtOAc) to afford(1r,3r)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)cyclobutanecarboxamide(26 mg, 42% yield) as a colorless oil

Step B:(1r,3r)-3-(4-(4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)cyclobutanecarboxamide(0.024 g, 0.044 mmol) was dissolved in MeOH (1.1 mL, 0.044 mmol) and theresulting yellow solution was treated with hydrochloric acid (5 to 6 Nsolution in 2-propanol; 0.18 mL, 0.88 mmol) and the reaction mixture wasstirred for 2 hours. The reaction mixture was treated with 3N NaOH(0.150 mL) and saturated aqueous NaHCO₃ until basic. The reactionmixture was diluted with EtOAc (10 mL) and the layers were separated.The reaction mixture was extracted with EtOAc and the combined organicextracts were dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified over silica gel (6% MeOH/CH₂Cl₂) to afford(1r,3r)-N-(2-hydroxyethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide(15 mg, 66% yield) as an off-white foam. Mass spectrum (apci) m/z=449.2(M+H). ¹H NMR (CDCl₃) δ 8.45 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 8.03(d, J=2.3 Hz, 1H), 8.01 (s, 1H), 8.00 (s, 1H), 6.95 (d, J=2.3 Hz, 1H),6.03 (t, J=5.1 Hz, 1H), 5.17 (pentet, J=7.8 Hz, 1H), 4.03 (m, 1H), 3.78(t, J=4.9 Hz, 2H), 3.50 (q, J=5.5 Hz, 2H), 3.12 (m, 1H), 2.99-2.77 (m,5H), 2.06-1.85 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 171.

Example Structure Name Data 172

(1s,3s)-N-(2- hydroxyethyl)-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)cyclobutanecarboxamide Mass spectrum (apci) m/z = 463.3 (M + H)

Example 173(S)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one

Step A:6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(30 mg, 0.080 mmol) was dissolved in CH₂Cl₂ (1 mL) and pyridine (25.7μL, 0.32 mmol) was added, followed by (S)-1-chloro-1-oxopropan-2-ylacetate (20.2 μL, 0.16 mmol). After stirring for 1 hour, the reactionmixture was quenched with water (0.1 mL) and concentrated. The residuewas purified by reverse phase chromatography (C18, 10-95% CH₃CN inwater) to afford(S)-1-oxo-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-2-ylacetate (25 mg, 64% yield).

Step B:(S)-1-Oxo-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-2-ylacetate (27 mg, 0.055 mmol) was dissolved in MeOH (2 mL). K₂CO₃ (2 mg,0.014 mmol) was added and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was diluted with Et₂O (20mL), filtered and concentrated to afford(S)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one(21 mg, 85% yield) as a colorless glass. Mass spectrum (apci) m/z=449.2(M+H). ¹H NMR (CDCl₃) δ 8.47 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=2.7 Hz,1H), 8.09 (s, 1H), 8.05 (m, 2H), 6.97 (dd, J=2.5, 1.0 Hz, 1H), 5.27 (m,1H), 4.75-4.51 (m, 4H), 4.29 (m, 1H), 4.04 (m, 1H), 3.32 (br s, 1H),2.06-1.86 (m, 4H), 1.40 (m, 3H), 0.86 (t, J=7.4 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 173.

Example Structure Name Data 174

2-hydroxy-1-(3-(4-(4-(1- (pentan-3-yl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1- yl)ethanone Mass spectrum(apci) m/z = 435.2 (M + H)

Example 175(R)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one

6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.05 g, 0.133 mmol) and D-lactic acid (0.0150 g, 0.166 mmol) were addedto DMF (1.90 mL, 0.133 mmol).(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (0.0657 g, 0.173 mmol) was added and the reactionmixture was allowed to stir for 24 hours. Water (10 mL) was added andthe reaction mixture was extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, and concentrated. The crude mixture waspurified over silica gel (0-6% MeOH w/NH₄OH in CH₂Cl₂) to afford(R)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one(0.0092 g, 0.0205 mmol, 15.4% yield) as a white solid. Mass spectrum(apci) m/z=449.2 (M+H). ¹H NMR (CDCl₃) δ 8.47 (s, 1H), 8.27 (s, 1H),8.16 (d, J=2.7 Hz, 1H), 8.09 (s, 1H), 8.05 (m, 2H), 6.97 (dd, J=2.5, 1.0Hz, 1H), 5.27 (m, 1H), 4.75-4.51 (m, 4H), 4.29 (m, 1H), 4.04 (m, 1H),3.32 (dd, J=11.2, 6.5 Hz, 1H), 2.06-1.86 (m, 4H), 1.40 (t, J=6.7 Hz,3H), 0.86 (t, J=7.4 Hz, 6H).

The following compounds were prepared according to the proceduredescribed for Example 175.

Example Structure Name Data 176

2-hydroxy-2-methyl-1-(3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1-yl)propan-1-one Mass spectrum (apci) m/z = 463.3 (M + H) 177

(1- hydroxycyclopropyl)(3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1-yl)methanone Mass spectrum (apci) m/z = 461.2 (M + H) 178

(cis-3- hydroxycyclobutyl)(3- (4-(4-(1-(pentan-3-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1-yl)methanone Mass spectrum (apci) m/z = 475.2 (M + H) 179

(trans-3- hydroxycyclobutyl)(3-(4- (4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1-yl)methanone Mass spectrum (apci) m/z = 475.2 (M + H)

Example 1802-(3-hydroxyazetidin-1-yl)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone

6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.050 g, 0.1328 mmol) and triethylamine (0.2036 mL, 1.461 mmol) wereadded to DMF (1 mL) and 2-chloroacetyl chloride (0.01321 mL, 0.1660mmol) was added. The reaction mixture was stirred for 1.5 hours.Azetidin-3-ol hydrochloride (0.1164 g, 1.063 mmol) was added and thereaction mixture was stirred for an additional 2 hours. Water (10 mL)was added and the reaction mixture was extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, and concentrated. Themixture was purified over silica gel (0-10% MeOH w/NH₄OH in CH₂Cl₂) toafford2-(3-hydroxyazetidin-1-yl)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone(0.0027 g, 0.005515 mmol, 4.152% yield) as a white solid. Mass spectrum(apci) m/z=490.2 (M+H). ¹H NMR (CDCl₃) δ 8.47 (d, J=1.0 Hz, 1H), 8.27(s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 8.03 (s,1H), 6.97 (dd, J=2.3, 1.0 Hz, 1H), 5.21 (m, 1H), 4.68 (d, J=6.7 Hz, 2H),4.58-4.45 (m, 3H), 4.04 (m, 1H), 3.83 (m, 2H), 3.27 (d, J=4.5 Hz, 2H),3.16 (m, 2H), 2.05-1.85 (m, 4H), 0.86 (t, J=7.4 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 180.

Example Structure Name Data 181

1-(3-(4-(4-(1-(pentan- 3-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)azetidin-1- yl)-2-(pyrrolidin-1-yl)ethanone Mass spectrum (apci) m/z = 488.3 (M + H)

Example 182N,N-dimethyl-2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)acetamide

6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(48 mg, 0.13 mmol) was stirred in CH₂Cl₂ (2 mL) and2-(dimethylamino)-2-oxoacetic acid (45 mg, 0.38 mmol),O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (49mg, 0.15 mmol) and diisopropylethylamine (26.7 μL, 0.15 mmol) wereadded. The reaction mixture was stirred at room temperature overnight.The reaction mixture was quenched with water and partitioned between 5%isopropyl alcohol in CH₂Cl₂ and 0.1 M NaOH with brine. The organic layerwas washed with a citric acid/brine mixture, dried over sodium sulfate,filtered and concentrated. The residue was purified by reverse phasechromatography (C18, 10 to 95% CH₃CN in water) to affordN,N-dimethyl-2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)acetamide(17 mg, 28% yield) as a colorless glass. Mass spectrum (apci) m/z=476.3(M+H). ¹H NMR (CDCl₃) δ 8.47 (d, J=1.0 Hz, 1H), 8.26 (s, 1H), 8.17 (s,1H), 8.11 (s, 1H), 8.04 (m, 2H), 6.97 (dd, J=2.5, 1.0 Hz, 1H), 5.25 (m,1H), 4.89 (ddd, J=11.0, 8.2, 1.4 Hz, 1H), 4.77 (dd, J=10.4, 5.5 Hz, 1H),4.64 (ddd, J=11.0, 8.2, 1.4 Hz, 1H), 4.57 (dd, J=11.2, 5.7 Hz, 1H), 4.04(m, 1H), 3.21 (s, 3H), 3.00 (s, 3H), 2.06-1.85 (m, 4H), 0.86 (t, J=7.4Hz, 6H).

Example 183(S)-3-amino-2-methyl-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.100 g, 0.311 mmol) and N-(tert-butoxycarbonyl)-3-iodo-L-alaninemethyl ester (0.205 g, 0.622 mmol) in DMF (1.6 mL) was added Cs₂CO₃(0.203 g, 0.622 mmol) and the mixture was stirred at 85° C. for 16hours. The reaction mixture was cooled to ambient temperature, dilutedwith water (15 mL) and stirred for 10 minutes. The mixture was extractedwith EtOAc and the combined extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified over silicagel (70% EtOAc/hexanes) to afford (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propanoate(100 mg, 62% yield) as a white foam.

Step B: To a solution of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propanoate(0.095 g, 0.18 mmol) in THF (0.91 mL, 0.18 mmol) at 0° C. was addedmethylmagnesium bromide (0.30 mL, 0.91 mmol) (3.0M Et₂O) and the mixturewas stirred at 0° C. for 2 hours and then at ambient temperature for 2hours. The reaction mixture was quenched by the addition of saturatedaqueous NH₄Cl (5 mL) and extracted with EtOAc (3×10 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified over silica gel (EtOAc) to afford (S)-tert-butyl(3-hydroxy-3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-yl)carbamate(70 mg, 74% yield) as a light yellow solid.

Step C: To a solution of (S)-tert-butyl(3-hydroxy-3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-yl)carbamate(0.066 g, 0.13 mmol) in EtOH (1.3 mL, 0.13 mmol) and THF (1.3 mL, 0.13mmol) was added hydrochloric acid, 5 to 6 N solution in 2-propanol (0.51mL, 2.5 mmol) and the mixture was stirred at ambient temperature for 7hours. The reaction mixture was treated with 3N NaOH (1 mL) and thensaturated aqueous NaHCO₃ was added until the reaction mixture was basic.The reaction mixture was diluted with EtOAc (10 mL) and the layers wereseparated. The aqueous layer was extracted with EtOAc and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified over silica gel (5-8% MeOH with NH₄OH/CH₂Cl₂) toafford(S)-3-amino-2-methyl-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol(44 mg, 82% yield) as a white foam. Mass spectrum (apci) m/z=423.2(M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=1.0 Hz, 1H), 8.27 (s, 1H), 8.17 (s,1H), 8.03 (m, 2H), 7.99 (s, 1H), 6.96 (dd, J=2.3, 0.8 Hz, 1H), 4.47 (dd,J=13.7, 3.1 Hz, 1H), 4.03 (m, 2H), 3.21 (dd, J=10.0, 3.3 Hz, 1H), 3.15(br s, 1H), 2.07-1.86 (m, 4H), 1.32 (s, 3H), 1.29 (s, 3H), 0.86 (t,J=7.2 Hz, 6H).

Example 1844-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol

Step A: To a stirred solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(80 mg, 0.249 mmol) in 1 mL of DMF at room temperature under nitrogenwas added NaH (11.9 mg, 0.299 mmol) (60% oil dispersion). After 10minutes, tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (69.0 mg,0.324 mmol) was added. The reaction mixture was heated to 65° C. andstirred overnight. The reaction mixture was quenched with saturatedammonium chloride solution (1 mL) and then partitioned between ethylacetate and water. The combined organic phases were isolated, washedwith brine, dried over MgSO₄, filtered and concentrated. The residue waspurified over silica gel (20-80% ethyl acetate in hexanes) to affordtert-butyl4-hydroxy-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate(66 mg, 50% yield) as a yellow solid.

Step B: To a stirred solution of tert-butyl4-hydroxy-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate(66 mg, 0.12 mmol) in 1 mL of dichloromethane at 0° C. in an open flaskwas added TFA (1 mL) and the reaction mixture was stirred for 1 hour.The reaction mixture was concentrated to dryness under a stream ofnitrogen and the residue was stirred in a mixture of dichloromethane (15mL) and 20% sodium carbonate solution (15 mL) for 5 minutes. The organicphases were isolated and the aqueous phase was extracted withdichloromethane. The combined organic layers were dried over MgSO₄,filtered and concentrated. The residue was purified over silica gel(eluent—gradient of 0%-20%-50% MeOH in CH₂Cl₂ with 2% NH₄OH) and theproduct was isolated and concentrated to dryness. The silica gel haddissolved in this high methanol chromatography solvent. The crudeproduct was filtered first through paper with dichloromethane and thenthrough a membrane filter. After concentration,4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol(39 mg, 69% yield) was isolated as a tan solid. Mass spectrum (apci)m/z=435.2 (M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=1.0 Hz, 1H), 8.26 (s, 1H),8.17 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 8.01 (s, 2H), 6.96 (dd, J=2.3, 1.0Hz, 1H), 5.30 (s, 1H), 4.17 (s, 2H), 4.03 (m, 1H), 3.06 (m, 2H), 2.93(dt, J=12.3, 3.9 Hz, 2H), 2.06-1.85 (m, 4H), 1.63 (m, 2H), 1.49 (m, 2H),0.85 (t, J=7.2 Hz, 6H).

Example 1851-(4-hydroxy-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanone

To a stirred solution of4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol(20 mg, 0.046 mmol) in 460 μL of dioxane and 460 μL of 20% sodiumcarbonate at 0° C. was added acetyl chloride (4.9 μL, 0.069 mmol). After1 hour, an additional 3 equivalents of acetyl chloride was added. Thereaction mixture was warmed to room temperature and stirred for anotherhour. The reaction mixture was partitioned between ethyl acetate andwater. The combined organic phases were washed with brine, dried overMgSO₄, filtered and concentrated. The residue was purified over silicagel (0-10% methanol in CH₂Cl₂) to afford1-(4-hydroxy-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanone(5 mg, 21% yield). Mass spectrum (apci) m/z=477.2 (M+H). ¹H NMR (CDCl₃)δ 8.47 (d, J⁼1.0 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 8.04 (d, J=2.5 Hz,1H), 8.02 (d, J=0.6 Hz, 1H), 7.98 (s, 1H), 6.96 (dd, J=2.3, 0.8 Hz, 1H),4.42 (m, 1H), 4.15 (s, 2H), 4.03 (m, 1H), 3.62 (m, 1H), 3.49 (m, 1H),3.05 (m, 1H), 2.10 (s, 3H), 2.05-1.86 (m, 4H), 1.52 (m, 4H), 0.86 (t,J=7.4 Hz, 6H).

Example 1862-amino-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone

6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(75 mg, 0.20 mmol), Et₃N (83.3 μL, 0.60 mmol) and2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)acetate (81.4 mg,0.30 mmol) were placed in CH₂Cl₂ (5 mL) and stirred for 1 hour. Waterwas added and the reaction mixture was extracted with CH₂Cl₂. Thecombined organic layers were concentrated. The residue was taken up in10% MeOH in CH₂Cl₂ and 4 N HCl in dioxane (2 mL) was added, and thereaction mixture was stirred for 2 hours. Saturated aqueous NaHCO₃ wasadded and the reaction mixture was extracted with 10% MeOH in CH₂Cl₂.The combined organic layers were concentrated. The residue was purifiedover silica gel (0-14% MeOH in CH₂Cl₂) followed by reverse phase (5-60%CH₃CN:water w/0.1% TFA) to provide the produce as the TFA salt. The TFAsalt was taken up in 10% MeOH in CH₂Cl₂ and saturated aqueous NaHCO₃ wasadded. The layers were separated and the organic layer was dried,filtered and concentrated to provide2-amino-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone(20.8 mg, 24% yield). Mass spectrum (apci) m/z=434.2 (M+H). ¹H NMR(CDCl₃) δ 8.47 (d, J=1.0 Hz, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 8.10 (s,1H), 8.04 (m, 2H), 6.97 (dd, J=2.3, 1.0 Hz, 1H), 5.24 (m, 1H), 4.65-4.49(m, 4H), 4.04 (m, 1H), 3.35 (d, J=4.7 Hz, 2H), 2.07-1.85 (m, 4H), 0.86(t, J=7.4 Hz, 6H).

Example 1872-(methylamino)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanonebis(2,2,2-trifluoroacetate)

Step A:6-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(60 mg, 0.16 mmol), Et₃N (66 μL, 0.48 mmol) and 2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)acetate (65 mg, 0.24 mmol) were placed inCH₂Cl₂ (3 mL) and stirred for 1 hour. Water was added and the mixturewas extracted with CH₂Cl₂. The organic layers were combined andconcentrated. The residue was purified by reverse phase chromatography(C18, 10-95% CH₃CN in water) to afford tert-butyl(2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethyl)carbamate(65 mg, 76% yield).

Step B: tert-Butyl(2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethyl)carbamate(46 mg, 0.086 mmol) was dissolved in DMF (2 mL) and 60% NaH (6.9 mg,0.17 mmol) was added and stirred for 2 hours. Mel (5.9 μL, 0.095 mmol)was added and stirred at room temperature overnight. The reactionmixture was quenched with water and extracted with EtOAc. The combinedorganic extracts were washed with water, dried over sodium sulfate,filtered and concentrated. The residue was purified by reverse phasechromatography (C18, 10-95% CH₃CN in water) to afford tert-butylmethyl(2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethyl)carbamate(23 mg, 48.7% yield).

Step C: tert-Butylmethyl(2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethyl)carbamate(22 mg, 0.040 mmol) was dissolved in CH₂Cl₂ (1 mL) and TFA (0.6 mL) wasadded and the reaction mixture was stirred for 1 hour. The reactionmixture was concentrated and placed under high vacuum to afford2-(methylamino)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanonebis(2,2,2-trifluoroacetate) (27 mg, 99% yield) as a yellow foam. Massspectrum (apci) m/z=448.2 (M+H).

Example 188(3R,4R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-3-ol

Step A: To a slurry of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.10 g, 0.31 mmol) in DMF(0.5 mL) was added Cs₂CO₃ (0.20 g, 0.62 mmol)and (1R,6S)-tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate(0.12 g, 0.62 mmol) and the reaction mixture was heated at 70° C.overnight. The reaction mixture was partitioned between EtOAc and water.The combined organic phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified over silica gel (0-100%EtOAc/CH₂Cl₂) to afford 2 spots. The top spot was determined to be(3R,4R)-tert-butyl3-hydroxy-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(50 mg, 31% yield).

Step B: To a solution of (3R,4R)-tert-butyl3-hydroxy-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.050 g, 0.096 mmol) in CH₂Cl₂ was added TFA (to a final concentrationof 1:1) and the reaction mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated in vacuo and azeotroped withEtOAc until a solid formed. The solid was collected to give(3R,4R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-3-ol(0.034 g, 0.081 mmol, 84% yield). Mass spectrum (apci) m/z=421.2 (M+H).¹H NMR (CD₂Cl₂) δ 8.40 (d, J=0.8 Hz, 1H), 8.19 (s, 1H), 8.14 (s, 1H),8.04 (s, H), 7.94 (d, J=2.3 Hz, 1H), 7.93 (s, 1H), 6.90 (dd, J=2.5, 1.0Hz, 1H), 3.97 (m, 2H), 3.81 (td, J=9.8, 4.9 Hz, 1H), 3.27 (ddd, J=12.1,4.9, 1.0 Hz, 1H), 3.12 (m, 1H), 2.67 (td, J=12.5, 2.7 Hz, 1H), 2.52 (dd,J=12.1, 10.0, 1H), 2.17 (m, 1H), 2.03-1.77 (m, 6H), 0.78 (t, J=7.4 Hz,6H).

Example 189(1S,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol

Step A: To a stirred solution oftrans-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol(90 mg, 0.22 mmol) in 2.2 mL THF at room temperature under nitrogen wasadded 4-nitrobenzoic acid (37 mg, 0.22 mmol) and PPh₃ (58 mg, 0.22mmol). Diisopropyl azodicarboxylate (43 μL, 0.22 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated to dryness and the crude material was purifiedover silica gel (0-50% EtOAc in hexanes) to afford2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentyl4-nitrobenzoate as a racemic mixture. The racemate was separated on aChiral Tech OJ-H column (4.6 mm×250 mm, 1:1 EtOH/hexanes, 1 mL/min):Peak A: 10.1 min. Arbitrarily assigned as (1S,2R) and Peak B: 14.5 min.Arbitrarily assigned as (1R,2S).

Step B: To a stirred solution of(1S,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentyl4-nitrobenzoate (26 mg, 0.0469 mmol) [Peak A from previous reaction] in1 mL of methanol at room temperature under nitrogen was added 2M aqueousK₂CO₃ (70.3 μL, 0.141 mmol) and the reaction mixture was stirredovernight. The reaction mixture was concentrated and partitioned betweenethyl acetate and water with stirring. The layers were separated, andthe organic layer was extracted with brine, dried over MgSO₄, filteredand concentrated to afford(1S,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol(Peak A) (17 mg, 85% yield) as a clear oil. Mass spectrum (apci)m/z=406.2 (M+H). ¹H NMR (CDCl₃) δ 8.45 (d, J=1.0 Hz, 1H), 8.26 (s, 1H),8.16 (s, 1H), 8.07 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 6.95(dd, J=2.5, 1.0 Hz, 1H), 4.52 (m, 2H), 4.03 (m, 1H), 3.53 (br s, 1H),2.35 (m, 1H), 2.23 (m, 1H), 2.11 (m, 1H), 2.05-1.85 (m, 6H), 1.77 (m,1H), 0.86 (t, J=7.2 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 189.

Example Structure Name Data 190

(1R,2S)-2-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1- yl)cyclopentanol Mass spectrum (apci) m/z= 406.2 (M + H)

Example 1912,2-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol

Step A: To a solution of4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(50 mg, 0.16 mmol) and methyl2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (65 mg, 0.31 mmol) in DMA(2 mL) was added cesium carbonate (101 mg, 0.31 mmol). The mixture wasstirred in a screw-cap vial at 100° C. overnight. The reaction mixturewas partitioned between water and EtOAc, and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic phases were washedwith water and brine, dried over Na₂SO₄, filtered and concentrated toafford methyl2,2-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propanoate(42 mg, 62% yield) as a white foam.

Step B: To a solution of methyl2,2-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propanoate(42 mg, 0.10 mmol) in methanol (1 mL) at 0° C. was added sodiumborohydride (100 mg, 2.65 mmol). The reaction mixture was allowed towarm slowly to room temperature overnight. The reaction mixture wastreated with saturated aqueous NH₄Cl (10 mL) and stirred for 10 minutes,then extracted with CH₂Cl₂. The combined organic phases were washed withbrine (5 mL), dried over Na₂SO₄ and concentrated. The residue waspurified over silica gel (20% acetone/CH₂Cl₂) to afford2,2-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol(25.5 mg, 65% yield) as a colorless glass. Mass spectrum (apci)m/z=408.2 (M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=1.0 Hz, 1H), 8.27 (s, 1H),8.16 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 6.95(dd, J=2.3, 1.0 Hz, 1H), 4.08 (s, 2H), 4.03 (m, 1H), 3.67 (t, J=6.8 Hz,1H), 3.25 (d, J=6.6 Hz, 2H), 2.06-1.86 (m, 4H), 1.00 (s, 6H), 0.86 (t,J=7.2 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 191.

Example Structure Name Data 192

(1-((4-(4-(1-(pentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1- yl)methyl)cyclopropyl)methanol Massspectrum (apci) m/z = 406.3 (M + H)

Example 193(2R)-3-(4-(4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: A solution of6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(250 mg, 0.67 mmol) and 1,1,1-trifluorobutan-2-yl methanesulfonate (208mg, 1.0 mmol) in DMA (5 mL) was treated with cesium carbonate (439 mg,1.35 mmol) then stirred at 80° C. in a sealed tube overnight. Thereaction mixture was treated with an additional 200 mg of1,1,1-trifluorobutan-2-yl methanesulfonate and stirred at 80° C. Thereaction mixture was partitioned between water and EtOAc and the aqueouslayer was extracted with EtOAc. The combined organic phases were washedwith water, and brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified over silica gel (10% acetone/CH₂Cl₂) to afford6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazineasa pale yellow gum.

Step B:6-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(29 mg, 0.06 mmol) was treated with TFA (1 mL) and stirred at 60° C.overnight. The mixture was concentrated and then partitioned betweenCH₂Cl₂ and 1N NaOH. The aqueous phase was extracted with CH₂Cl₂ and thecombined organic phases were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified over silica gel(2.5% MeOH/CH₂Cl₂) to afford6-(1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(12 mg, 55% yield) as a white solid.

Step C: To a solution of6-(1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(12 mg, 0.03 mmol) in DMA (1 mL) was added(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (9 μL, 0.07 mmol)followed by cesium carbonate (22 mg, 0.07 mmol). The reaction mixturewas stirred at 70° C. overnight. Additional(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (50 μL) was added andthe reaction mixture stirred overnight at 70° C. The reaction mixturewas partitioned between water and EtOAc and the aqueous layer extractedwith EtOAc. The combined organic phases were washed with water andbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified over silica gel (10% acetone/CH₂Cl₂) to afford6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(8 mg, 50.6% yield) as a colorless glass.

Step D:6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(8 mg, 0.02 mmol) was dissolved in isopropyl alcohol (1 mL) andconcentrated HCl (1 drop) was added. The reaction mixture was stirred at60° C. for 2 hours. The cooled reaction mixture was concentrated andpartitioned between 2N NaOH and CH₂Cl₂. The aqueous layer was extractedwith CH₂Cl₂ and the combined organic phases were washed with brine,dried over Na₂SO₄ and concentrated to afford(2R)-3-(4-(4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(4.7 mg, 64% yield) as a white solid. Mass spectrum (apci) m/z=436.2(M+H). ¹H NMR (CDCl₃) δ 8.50 (d, J=0.8 Hz, 1H), 8.32 (s, 1H), 8.28 (s,1H), 8.06 (m, 2H), 8.00 (s, 1H), 6.95 (dd, J=2.5, 0.8 Hz, 1H), 4.73 (m,1H), 4.40-4.29 (m, 2H), 4.13 (m, 1H), 3.68-3.58 (m, 2H), 2.41-2.18 (m,2H), 0.98 (t, J=7.2 Hz, 3H).

Examples 194 and 195(R)-3-(4-(4-(1-((R)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diolhydrochloride and(R)-3-(4-(4-(1-((S)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diolhydrochloride

Step A: A mixture of4-chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (60 mg, 0.159 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazole(55.8 mg, 0.183 mmol), Pd₂dba₃ (14.6 mg, 0.0159 mmol), XPHOS (15.2 mg,0.0319 mmol) in 2M K₂CO₃ (239 μL, 0.478 mmol) and dioxane (797 μL, 0.159mmol) was degassed with nitrogen and heated to 80° C. overnight. Thereaction mixture was partitioned between water and EtOAc, dried overNa₂SO₄, filtered and concentrated. The residue was purified over silicagel (10-50% EtOAc in CH₂Cl₂) to afford6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(60 mg, 78.1% yield).

Step B: A solution of6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(60 mg, 0.12 mmol) in TFA (1246 μL, 0.12 mmol). Triflic acid (11 μL,0.12 mmol) was added and the reaction mixture was heated at 80° C. for24 hours. The reaction mixture was concentrated and taken on to nextstep without purification.

Step C:6-(1H-Pyrazol-4-yl)-4-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(60 mg, 0.166 mmol) was dissolved in DMF (0.8 mL) and Cs₂CO₃ (108 mg,0.332 mmol) and (S)-(−)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane(27.5 mg, 0.183 mmol) were added. The reaction mixture was heated to 80°C. overnight. The reaction mixture was partitioned between water andEtOAc, washed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified over silica gel to afford6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazineas a diastereomeric mixture.

Step D: Diastereomeric separation of the mixture prepared in Step C wasachieved by a Chiral Tech IA column, eluting with 30% EtOH in hexanes toafford 2 peaks:6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-((R)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(first eluting peak) and6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-((S)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(second eluting peak). Absolute stereochemistry was arbitrarilyassigned.

Step E: The purified diastereomers isolated in Step D were separatelydissolved in MeOH (1 mL) and treated with 20 μL concentrated HCl for 4hours. The solutions were concentrated to separately afford(R)-3-(4-(4-(1-((R)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diolhydrochloride salt (Peak A) (6.2 mg, 65% yield); Mass spectrum (apci)m/z=436.1 (M+H); and(R)-3-(4-(4-(1-((S)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diolhydrochloride salt (Peak B) (5.5 mg, 72% yield). Mass spectrum (apci)m/z=436.1 (M+H).

The following compounds were prepared according to the proceduredescribed for Examples 194 and 195.

Example Structure Name Data 196

(R)-3-(4-(4-(1-((R)-1- cyclobutylpropyl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 422.2 (M + H) 197

(R)-3-(4-(4-(1-((S)-1- cyclobutylpropyl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z = 422.2 (M + H)

Examples 198 and 199(R)-3-(4-(4-(1-((S)-2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-dioland(R)-3-(4-(4-(1-((R)-2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: A mixture of4-chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (500 mg, 1.33 mmol),3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pentan-2-one(481 mg, 1.73 mmol), Pd₂dba₃ (122 mg, 0.133 mmol), XPHOS (127 mg, 0.266mmol) in 2M K₂CO₃ (1993 μL, 3.99 mmol) and dioxane (6645 L, 1.33 mmol)was degassed with nitrogen and heated at 80° C. overnight. The reactionmixture was partitioned between water and EtOAc, dried over sodiumsulfate, filtered and concentrated. The residue was purified over silicagel (0-100% EtOAc in CH₂Cl₂) to afford3-(4-(6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)pentan-2-one.

Step B: To a solution of3-(4-(6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)pentan-2-one(350 mg, 0.768 mmol) in CH₂Cl₂ (3842 μL, 0.768 mmol) in a Teflon bottle(50 mL) at 0° C. was added Diethylaminosulfur trifluoride (DAST) (305μl, 2.31 mmol) and the resulting mixture was heated to 40° C. for 3hours. The reaction mixture was transferred to a glass round bottomflask and concentrated. The residue was purified over silica gel (0-5%MeOH in CH₂Cl₂) to afford4-(1-(2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(300 mg, 82% yield).

Step C:4-(1-(2,2-Difluoropentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(60 mg, 0.125 mmol) was heated in TFA (2 mL) withtrifluoromethanesulfonic acid (100 μL) to 50° C. for 2 hours. Thereaction mixture was concentrated and used in the next step withoutpurification.

Step D: A suspension of4-(1-(2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(50 mg, 0.140 mmol), (S)-(−)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane(28.7 μL, 0.210 mmol), Cs₂CO₃ (137 mg, 0.420 mmol) in DMF (0.7 mL) washeated at 60° C. for 3 days. The reaction mixture was partitionedbetween water and EtOAc, washed with water and brine, dried over sodiumsulfate, filtered and concentrated. The residue was purified over silicagel to afford(2R)-3-(4-(4-(1-(2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(22 mg, 36% yield) as a diastereomeric mixture.

Step E: The diastereomers prepared in Step D were separated by chiralchromatography (Chiral Tech IA column, 4.6 mm×250 mm, 5 micron, 25% EtOHin hexanes, 1 mL/min). The absolute chirality of the isolated compoundswas arbitrarily assigned. Peak A: 7 mg; retention time=16.7 min; Massspectrum (apci) m/z=432.2 (M+H). ¹H NMR (CDCl₃) δ 8.47 (s, 1H), 8.28 (s,1H), 8.24 (s, 1H), 8.04 (m, 2H), 7.99 (s, 1H), 6.93 (m, 1H), 4.43 (m,1H), 4.35 (d, J=5.3 Hz, 2H), 4.17 (pentet, J=4.9 Hz, 1H), 3.73-3.63 (m,2H), 3.55 (br s, 1H), 2.31-2.12 (m, 2H), 1.65-1.50 (m, 3H), 0.92 (t,J=7.2 Hz, 3H). Peak B: 6 mg; retention time=18.1 min retention time;Mass spectrum (apci) m/z=432.2 (M+H). ¹H NMR (CDCl₃) δ 8.47 (s, 1H),8.28 (s, 1H), 8.24 (s, 1H), 8.04 (m, 2H), 7.99 (s, 1H), 6.93 (m, 1H),4.43 (m, 1H), 4.35 (d, J=5.1 Hz, 2H), 4.17 (pentet, J=4.7 Hz, 1H),3.72-3.63 (m, 2H), 3.55 (br s, 1H), 2.47 (br s, 1H), 2.32-2.13 (m, 2H),1.65-1.50 (m, 3H), 0.92 (t, J=7.4 Hz, 3H).

Example 200(S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,3-diol

Step A: To the solid4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.40 g, 1.2 mmol) and Cs₂CO₃ (0.81 g, 2.5 mmol) was added DMF (5 mL)followed by 4-(chloromethyl)-1,3-dioxane (0.34 g, 2.5 mmol) and thereaction mixture was stirred at 80° C. overnight. The reaction mixturewas poured into water and extracted into EtOAc. The combined organicphases were washed with brine, dried over MgSO₄ and concentrated invacuo. The residue was purified over silica gel (0-100% EtOAc in CH₂Cl₂)to afford6-(1-((1,3-dioxan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.4 g, 0.95 mmol, 76% yield).

Step B: To6-(1-((1,3-dioxan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.4 g, 0.9 mmol) was added 5M HCl in isopropyl alcohol and the reactionmixture was heated to 80° C. overnight. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between EtOAc and1N NaOH. The combined organic phases were washed with brine, dried overMgSO₄ and concentrated in vacuo. The material purified over silica gel(0-10% MeOH/CH₂Cl₂) and precipitated from CH₃CN to afford4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,3-diol(0.2 g, 0.5 mmol, 51% yield).

Step C: To a solution of4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,3-diol(0.187 g, 0.457 mmol) in CH₂Cl₂ (5 mL) was added 1H-imidazole (0.124 g,1.83 mmol) and tert-butylchlorodimethylsilane (0.206 g, 1.37 mmol) andthe reaction mixture was stirred overnight. The reaction mixture waswashed with 1N HCl, brine, dried over MgSO₄ and concentrated in vacuo.The material was purified over silica gel (0-50% EtOAc/CH₂Cl₂) to afford6-(1-(2,4-bis((tert-butyldimethylsilyl)oxy)butyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.10 g, 0.157 mmol, 34.3% yield) as an enantiomeric mixture.

Step D: The enantiomers prepared in Step C were separated by chiralchromatography (Chiral Tech AS-H column, 4.6 mm×250 mm, 5 micron, 15%EtOH in hexanes, 1 mL/min). Peak A, 5.6 min retention time. Peak B, 6.9min retention time. Peak A was arbitrarily assigned as(S)-6-(1-(2,4-bis((tert-butyldimethylsilyl)oxy)butyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine.

Step E: To(S)-6-(1-(2,4-bis((tert-butyldimethylsilyl)oxy)butyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.010 g, 0.016 mmol) was added 5M HCl in isopropyl alcohol and thereaction mixture was heated to 60° C. for 2 hours. The reaction mixturewas concentrated in vacuo and the residue was partitioned between EtOAcand basic water. The combined organic phases were washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purifiedover silica gel (0-10% MeOH/CH₂Cl₂) to afford(S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,3-diol(Peak A) (0.0041 g, 0.010 mmol, 64% yield). Mass spectrum (apci)m/z=410.2 (M+H). ¹H NMR (CDCl₃) δ 8.45 (d, J=0.8 Hz, 1H), 8.26 (s, 1H),8.25 (s, 1H), 8.07 (s, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.98 (s, 1H), 6.98(dd, J=2.3, 0.8 Hz, 1H), 4.35 (br s, 1H), 4.31 (dd, J=13.5, 2.7 Hz, 1H),4.21 (dd, J=13.7, 7.4 Hz, 1H), 4.04 (m, 1H), 3.91 (t, J=5.3 Hz, 2H),2.06-1.85 (m, 4H), 1.81-1.74 (m, 2H), 0.86 (t, J=7.2 Hz, 6H).

The following compound was prepared according to the procedure describedfor Example 200.

Example Structure Name Data 201

(R)-4-(4-(4-(1-(pentan-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)butane-1,3- diol Mass spectrum (apci)m/z = 422.2 (M + H)

Example 202(R)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A:4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(250 mg, 0.778 mmol), Cs₂CO₃ (760 mg, 2.33 mmol) and(2,2,4-trimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (174 mg,0.778 mmol) were placed in DMF (8 mL) and heated to 70° C. for 18 hours.Water was added and the reaction mixture was extracted with EtOAc. Theorganic layers were combined and washed with water. The organic layerwas concentrated and the residue was purified over silica gel (0-60EtOAc in hexanes) to afford4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-((2,2,4-trimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(325 mg, 0.723 mmol, 92.9% yield) as an isomeric mixture.

Step B:4-(1-(Pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-((2,2,4-trimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(325 mg, 0.723 mmol) was purified by chiral chromatography on a ChiralTech IA column (4.6 mm×250 mm, 5 micron), eluting with 20% EtOH:80%hexanes at 1 mL/min. Peak A (14.9 min), arbitrarily assigned as the Risomer; and Peak B (20.9 min), arbitrarily assigned as the S isomer.

Step C: To a solution of(R)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-((2,2,4-trimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(107 mg, 0.238 mmol) [Peak A from previous step] in 5 mL of isopropylalcohol was added 6 drops of HCl and the reaction mixture was stirredfor 1 hour at 70° C. The reaction mixture was concentrated and taken upin CH₂Cl₂. Saturated bicarbonate was added and the reaction mixture wasextracted with CH₂Cl₂. The organic layers were combined andconcentrated. The residue was purified over silica gel (0-9% MeOH inCH₂Cl₂) to provide(R)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(Peak A) (73.9 mg, 0.180 mmol, 75.8% yield). Mass spectrum (apci)m/z=410.2 (M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=0.8 Hz, 1H), 8.26 (s, 1H),8.16 (s, 1H), 8.03 (m, 2H), 8.02 (s, 1H), 6.96 (dd, J=2.3, 0.8 Hz, 1H),4.34 (d, J=14.1 Hz, 1H), 4.18 (d, J=14.1 Hz, 1H), 4.03 (m, 1H), 3.57 (s,1H), 3.52 (dd, J=11.5, 6.7 Hz, 1H), 3.39 (dd, J=11.3, 6.7 Hz, 1H), 2.80(t, J=6.7 Hz, 1H), 2.05-1.85 (m, 4H), 1.22 (s, 3H), 0.86 (t, J=7.4 Hz,6H).

The following compound was prepared according to the procedure describedfor Example 202.

Example Structure Name Data 203

(S)-2-methyl-3-(4-(4-(1- (pentan-3-yl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Mass spectrum (apci)m/z= 410.2 (M + H)

Example 204(R)-3-(4-(4-(1-((R)-1-((S)-2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: A pressure tube equipped with a stir bar was charged with4-chloro-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (0.100 g, 0.455mmol) and 3 mL of dioxane. To this was added1-(1-(2,2-difluorocyclopropyl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.284 g, 0.911 mmol, 2 mL in dioxane), Pd₂dba₃ (0.0417 g, 0.0455 mmol),XPhos (0.0868 g, 0.182 mmol) and K₂CO₃ (0.911 mL, 1.82 mmol, 2M). Thetube was sealed and warmed to 100° C. for 16 hours. The mixture waspartitioned between water and EtOAc and filtered through GF/F filterpaper. The filtrate was extracted with EtOAc, and the combined organicextracts were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified over silica gel (EtOAc) to afford4-(1-(1-(2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(52 mg, 31% yield) as a tan solid.

Step B: A round bottom flask equipped with a stir bar and nitrogen inletwas charged with4-(1-(1-(2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.052 g, 0.141 mmol), 2 mL of DMA and cesium carbonate (0.138 g, 0.422mmol). To this was added (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane(0.042 g, 0.282 mmol) and the reaction mixture was warmed to 70° C. for6 hours. The reaction mixture was diluted with water and extracted withEtOAc. The combined organic extracts were washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified over silica gel (EtOAc) to afford 35 mg of the product as adiastereomeric mixture.

Step C: The diastereomers prepared in Step B were separated by chiralchromatography (Chiral Tech OJ-H, 2.1 cm×250 mm, 20% EtOH in hexanes, 24mL/min) to afford 2 peaks that were arbitrarily assigned chirality. PeakA (retention time=16 min), arbitrarily assigned as4-(1-((1R)-1-(2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)-6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;and Peak B (retention time=20 min), arbitrarily assigned as4-(1-((1R)-1-(2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)-6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine.

Step X: A microwave reaction tube was charged with4-(1-((1R)-1-(2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)-6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.012 mg, 0.025 mmol) [Peak A from previous step] and isopropyl alcohol(1 mL). To this was added a couple of drops of concentrated HCl. Thetube was sealed and the reaction mixture was warmed to 60° C. for 3hours. The reaction mixture was concentrated under reduced pressure andthe crude material was taken up in 25% isopropyl alcohol/CH₂Cl₂ and 10%aqueous K₂CO₃. The mixture was extracted with 25% isopropylalcohol/CH₂Cl₂, and the combined organic extracts were dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford(R)-3-(4-(4-(1-((R)-1-((S)-2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(Peak A”) (7 mg, 64% yield) as a solid. Mass spectrum (apci) m/z=444.2(M+H). ¹H NMR (CD₃OD) δ 8.70 (d, J=0.8 Hz, 1H), 8.63 (s, 1H), 8.38 (s,1H), 8.28 (s, 1H), 8.10 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.20 (dd,J=2.3, 0.8 Hz, 1H), 4.37 (dd, J=13.9, 4.1 Hz, 1H), 4.20 (dd, J=14.1, 7.6Hz, 1H), 4.05 (m, 2H), 3.60-3.51 (m, 2H), 2.38-2.13 (m, 2H), 2.09-1.97(m, 1H), 1.59-1.48 (m, 1H), 1.37-1.25 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).

The following compounds were prepared according to the proceduredescribed for Example 204.

Example Structure Name Data 205

(R)-3-(4-(4-(1-((S)-1- cyclopropylbutan-2-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Massspectrum (apci) m/z = 422.2 (M + H) 206

(R)-3-(4-(4-(1-((R)-1- cyclopropylbutan-2-yl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Massspectrum (apci) m/z = 422.2 (M + H)

Example 207(R)-3-(4-(4-(1-((1S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: In 8 mL of DMF were combined4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.72 g,8.84 mmol), 1-cyclobutylpropyl methanesulfonate (1.7 g, 8.84 mmol), andCs₂CO₃ (3.02 g, 9.28 mmol) and the reaction mixture was sparged withargon for 5 minutes before vessel was sealed and heated to 100° C. overthe weekend. The reaction mixture was poured into saturated sodiumbicarbonate and extracted with EtOAc. The combined organic layers werewashed with 1:1 bicarbonate:water and brine, and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by silica gel chromatography eluting 3% acetone in CH₂Cl₂to afford an inseparable mixture of1-(1-cyclobutylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand1-(trans-2-ethylcyclopentyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.353 g, 14% yield).

Step B: In 5 mL of THF were combined the mixture of1-(1-cyclobutylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand1-(trans-2-ethylcyclopentyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.353 g, 1.22 mmol).4-Chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (0.458 g, 1.22 mmol), Pd₂(dba)₃ (0.0557 g, 0.0608 mmol),and XPhos (0.116 g, 0.243 mmol) were added and the reaction mixture wassparged with argon for 2 minutes. K₂CO₃ (2.43 mL, 4.87 mmol) was addedand the reaction mixture was sparged for another 3 minutes before thevessel was sealed and heated to 70° C. overnight. The reaction mixturewas diluted with EtOAc (30 mL) and 10 mL of water, and the organic layerwas collected and dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue was purified over silica gel (20% acetonein CH₂Cl₂), followed by reverse phase chromatography (C18, 5 to 95%CH₃CN in water) to afford4-(1-(2-ethylcyclopentyl)-1H-pyrazol-4-yl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.150 g, 0.321 mmol, 26.4% yield).

Step C:4-(1-(2-Ethylcyclopentyl)-1H-pyrazol-4-yl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.150 g, 0.321 mmol) was dissolved in 1 mL of TFA and the reactionmixture was heated to 80° C. overnight and then concentrated underreduced pressure. The residue was taken up in 1M NaOH and extracted withEtOAc. The combined organic layers were washed with brine (10 mL), driedover MgSO₄, filtered, and removed under reduced pressure to provide4-(1-(2-ethylcyclopentyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazineas a racemic mixture.

Step D: The racemic mixture prepared in Step C was purified by chiralchromatography (Chiral Tech OD-H, 4.6 mm×250 mm, 5 micron, 10% EtOH inhexanes, 1 mL/min) to afford two peaks that were arbitrarily assigned.Peak A (retention time=14.4 min):4-(1-((1S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine,and Peak B (retention time=17.1 min):4-(1-((1R,2S)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

Step E: To a solution of4-(1-((1S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(7 mg, 0.02 mmol) in DMA (0.5 mL) was added(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (14 μL, 0.10 mmol)followed by cesium carbonate (13 mg, 0.04 mmol). The mixture was stirredat 70° C. in a sealed screw-cap vial overnight. The mixture waspartitioned between water (5 mL) and EtOAc (5 mL) and the aqueous layerextracted with EtOAc. The combined organic phases were washed with waterand brine, then dried over Na₂SO₄, filtered and concentrated to afford6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-((1S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazineas a colorless glass.

Step F:6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-((1S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(9 mg, 0.02 mmol) was dissolved in isopropyl alcohol (1 mL) andconcentrated HCl (1 drop) was added. The mixture was stirred at 60° C.for 2 hours. The cooled mixture was concentrated and the residue waspartitioned between 2N NaOH and CH₂Cl₂. The aqueous layer was extractedwith CH₂Cl₂ and the combined organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedover silica gel (2-5% MeOH/CH₂Cl₂) to afford(R)-3-(4-(4-(1-((1S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(Peak A) (3.8 mg, 46% yield) as a white solid. Mass spectrum (apci)m/z=422.2 (M+H). ¹H NMR (CDCl₃) δ 8.46 (d, J=0.8 Hz, 1H), 8.22 (s, 1H),8.14 (s, 1H), 8.06 (s, 1H), 8.03 (s, J=2.5 Hz, 1H), 7.99 (s, 1H), 6.94(dd, J=2.4, 0.8 Hz, 1H), 4.81 (td, J=7.2, 5.1 Hz, 1H), 4.39-4.27 (m,2H), 4.11 (m, 1H), 3.66-3.56 (m, 2H), 2.40-2.22 (m, 2H), 2.16-2.05 (m,2H), 2.02-1.94 (m, 1H), 1.83-1.57 (m, 2H), 1.17-1.09 (m, 1H), 0.94-0.82(m, 4H).

The following compound was prepared according to the procedure describedfor Example 207.

Example Structure Name Data 208

(R)-3-(4-(4-(1-((1R,2S)- 2-ethylcyclopenlyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Massspectrum (apci) m/z = 422.2 (M + H)

Example 209(R)-3-(4-(4-(1-((R)-1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: A mixture of4-chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazinehydrochloride (0.322 g, 0.855 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazole(0.272 g, 0.855 mmol), Pd₂dba₃ (0.0783 g, 0.0855 mmol), XPhos (0.0815 g,0.171 mmol) in 2M K₂CO₃ (1.28 mL, 2.56 mmol) and dioxane (4.27 mL, 0.855mmol) was degassed with nitrogen and heated at 100° C. for 2 hours. Thereaction mixture was partitioned between EtOAc and brine. The aqueouslayer was extracted with EtOAc. The combined organic layers were driedover sodium sulfate, filtered and concentrated. The residue was purifiedover silica gel (10-80% EtOAc in hexanes) to afford6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(339 mg, 80% yield).

Step B: A solution of6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(339 mg, 0.684 mmol) in TFA (6842 μL, 0.684 mmol) was heated at 80° C.for 30 minutes. Triflic acid (60.8 μL, 0.684 mmol) was added and thereaction heated overnight. The reaction mixture was concentrated,partitioned between EtOAc and saturated aqueous NaHCO₃, dried oversodium sulfate, filtered and concentrated to afford crude6-(1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine,which was taken on to the next step without further purification.

Step C: A suspension of6-(1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(300 mg, 0.799 mmol),(S)-(−)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (120 μL, 0.879mmol), Cs₂CO₃ (521 mg, 1.60 mmol) in DMF (3996 μL, 0.799 mmol) washeated at 60° C. for 1 day. The reaction mixture was diluted with EtOAcand then washed with water. The organic layer was dried over sodiumsulfate and concentrated to afford6-(1-((-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazineas a mixture of diastereomers. The diastereomers were separated bychiral chromatography (Chiral Tech IA column, 4.6 mm×250 mm, 5 micron,15% EtOH in hexanes, 1 mL/min) to afford Peak A (retention time=21.5min), arbitrarily assigned as R stereochemistry; and Peak B (retentiontime=24.3 min), arbitrarily assigned as S stereochemistry.

Step D: A solution of6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(42 mg, 0.086 mmol) [Peak A from previous step] and concentrated HCl (3drops) in methanol was heated at 65° C. for 1 hour. The mixture wasconcentrated and purified by reverse phase chromatography (C18, 5 to 95%CH₃CN in water) to afford(R)-3-(4-(4-(1-((R)-1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(Peak A) (33 mg, 86% yield). Mass spectrum (apci) m/z=450.2 (M+H). ¹HNMR (CD₃OD) δ 8.63 (s, 1H), 8.55 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H),8.08 (s, 1H), 8.06 (s, J=2.5 Hz, 1H), 7.14 (dd, J=2.5, 0.8 Hz, 1H), 4.62(m, 1H), 4.39 (dd, J=14.1, 4.3 Hz, 1H), 4.23 (dd, J=14.1, 7.4 Hz, 1H),4.07 (m, 1H), 3.62-3.52 (m, 2H), 3.11-2.96 (m, 1H), 2.80-2.66 (m, 1H),2.15-1.91 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).

The following compounds were prepared according to the proceduredescribed for Example 209.

Example Structure Name Data 210

(R)-3-(4-(4-(1-((S)-1,1,1- trifluoropentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Massspectrum (apci) m/z = 450.2 (M + H) 211

(R)-2-(4-(4-(1-(1,1,1- trifluoropentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Massspectrum (apci) m/z = 450.2 (M + H) 212

(S)-2-(4-(4-(1-(1,1,1- trifluoropentan-3-yl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Massspectrum (apci) m/z = 450.2 (M + H)

Example 213(R)-3-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: In 80 mL of THF were combined4-chloro-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (6.5 g, 30 mmol),1-(1-cyclopropylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(12 g, 44 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (2.8g, 5.9 mmol), and Pd₂(dba)₃ (1.4 g, 1.5 mmol). The reaction mixture wassparged with argon for 3 minutes. To the reaction mixture was addedpotassium carbonate (44 mL, 89 mmol) by syringe and the reaction mixturewas sparged for another 5 minutes before the vessel was sealed andheated to 75° C. for 5 hours. The cooled reaction mixture was extractedwith EtOAc and CH₂Cl₂. The organic layer was passed over a plug of 1:1Celite®:MgSO₄ and concentrated under reduced pressure to yield a thickoil. This oil was triturated with 10 volumes of CH₂Cl₂ (65 mL) and theresulting solids were washed with CH₂Cl₂ (30 mL). The filtrate wasconcentrated and purified over silica gel (15-30% acetone in CH₂Cl₂) toafford a racemic mixture of4-(1-(1-cyclopropylpropyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(4.9 g, 13 mmol, 45% yield) as a light yellow foam.

Step B: The racemic mixture prepared in Step A was separated by chiralSFC chromatography (IA column, 2.0×25 cm, 20% MeOH (0.1% DEA) in CO₂,100 bar, 70 mL/min) to afford 2 compounds. Peak A:(S)-4-(1-(1-cyclopropylpropyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine:5.2 min retention time. Peak B:(R)-4-(1-(1-cyclopropylpropyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine,6.1 min retention time. Absolute stereochemistry was arbitrarilyassigned.

Step C: To a solution of(R)-4-(1-(1-cyclopropylpropyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(1.1 g, 3.3 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.2 g, 6.6 mmol) and(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.90 mL, 6.6 mmol) andthe reaction mixture was heated to 70° C. overnight. The reactionmixture was diluted with EtOAc and washed with water and brine, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedover silica gel (0-50% EtOAc/CH₂Cl₂ as eluent) to afford4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)-6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(1.1 g, 2.5 mmol, 74% yield).

Step D: To a solution of4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)-6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(1.1 g, 2.5 mmol) in isopropyl alcohol (20 mL) was added 5 drops ofconcentrated HCl and the reaction mixture was heated to 70° C. for 5hours. The reaction mixture was concentrated in vacuo and the residuewas partitioned between basic water and EtOAc. The combined organicphases were washed with brine, dried over MgSO₄ and concentrated invacuo. The residue was purified over silica gel (0-10% MeOH/ETOAc) toafford(R)-3-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(Peak B) (0.79 g, 1.9 mmol, 79% yield). Mass spectrum (apci) m/z=408.2(M+H). ¹H NMR (d₆-DMSO) δ 8.99 (d, J=0.8 Hz, 1H), 8.72 (d, J=0.6 Hz,1H), 8.37 (s, 1H), 8.33 (d, J=0.6 Hz, 1H), 8.16 (d, J=2.5 Hz, 1H), 8.15(d, J=0.6 Hz, 1H), 7.35 (dd, J=2.5, 1.0 Hz, 1H), 5.04 (d, J=5.3 Hz, 1H),4.76 (t, J=5.7 Hz, 1H), 4.28 (dd, J=13.7, 3.9 Hz, 1H), 4.04 (dd, J=13.7,7.8 Hz, 1H), 3.88 (m, 1H), 3.51 (td, J=9.2, 5.1 Hz, 1H), 3.44-3.33 (m,2H), 2.16-1.95 (m, 2H), 1.40 (m, 1H), 0.79 (t, J=7.2 Hz, 3H), 0.67 (m,1H), 0.46-0.30 (m, 3H).

The following compounds were prepared according to the proceduredescribed for Example 213.

Example Structure Name Data 214

(R)-3-(4-(4-(1-((S)-1- cyclopropylpropyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,2- diol Massspectrum (apci) m/z = 408.2 (M + H) 215

(R)-2-(4-(4-(1-(1- cyclopropylpropyl)-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- pyrazol-1-yl)propane-1,3- diol Mass spectrum (apci)m/z = 408.2 (M + H)

Example 216(R)-3-(4-(4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: To a solution of1-(dicyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.3 g, 4.6 mmol) in THF (40 mL) was added sodium hydrogen carbonate(7.6 mL, 11 mmol) and4-chloro-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (0.5 g, 2.3 mmol)and the reaction mixture was purged with N₂ for 20 minutes. To thereaction mixture was added 100 mg each of Pd₂(dba)₃ and XPhos and thereaction mixture was heated to 83° C. for 4 hours. The cooled reactionmixture was partitioned between EtOAc and water, washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purifiedover silica gel (20-100% EtOAc in CH₂Cl₂) to afford4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine.

Step B: To a solution of4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.10 g, 0.29 mmol) in DMF (4 mL) was added(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.087 g, 0.58 mmol) andCs₂CO₃ (0.19 g, 0.58 mmol) and the reaction mixture was stirredovernight at 80° C. The reaction mixture was partitioned between EtOAcand water. The combined organic phases were washed with brine, driedover MgSO₄ and concentrated in vacuo. The residue was purified oversilica gel (0-100% EtOAc/CH₂Cl₂) to afford(R)-4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)-6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.05 g, 0.11 mmol, 38% yield)

Step C: To a solution of(R)-4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)-6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.050 g, 0.109 mmol) in isopropyl alcohol (10 mL) was addedconcentrated HCl (3 drops) and the reaction mixture was stirredovernight at room temperature. The reaction mixture was concentrated invacuo and the residue was partitioned between EtOAc and 1N NaOH. Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified over silica gel (0-10%MeOH/CH₂Cl₂) to afford(R)-3-(4-(4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(0.0193 g, 0.0460 mmol, 42.3% yield). Mass spectrum (apci) m/z=420.2(M+H). ¹H NMR (CDCl₃) δ 8.43 (d, J=0.8 Hz, 1H), 8.32 (s, 1H), 8.22 (s,1H), 8.04 (s, 1H), 8.02 (d, J=2.5 Hz, 1H), 7198 (s, 1H), 6.95 (dd,J=2.5, 1.0 Hz, 1H), 4.35 (s, 1H), 4.33 (d, J=1.2 Hz, 1H), 4.16 (pentet,J=5.3 Hz, 1H), 3.71-3.63 (m, 2H), 3.13 (t, J=8.6 Hz, 1H), 1.48-1.39 (m,2H), 0.77 (m, 2H), 0.58 (m, 2H), 0.53-0.39 (m, 4H).

Example 217(R)-3-(4-(4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol

Step A: To a stirred solution of1-(cis-2-methylcyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(91 mg, 0.35 mmol) in 1 mL of dioxane in a capped reaction vial wasadded 4-chloro-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (76 mg, 0.35mmol), 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (17mg, 0.035 mmol) and 2M aqueous K₂CO₃ (347 μL, 0.69 mmol). The reactionmixture was sparged with argon for 5 minutes and then Pd₂(dba)₃ (16 mg,0.017 mmol) was added. The vial was capped and heated to 80° C.overnight. The reaction mixture was cooled to room temperature andpartitioned between dichloromethane (15 mL) and water (15 mL). Thecombined organic phases were isolated and the aqueous phase wasextracted with dichloromethane. The combined organic layers were driedover MgSO₄, filtered and concentrated. The residue was purified oversilica gel (10-75% EtOAc in hexanes) to afford4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(17 mg, 15% yield) as a yellow solid.

Step B: To a stirred solution of4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(17 mg, 0.05323 mmol) in 400 μL of DMF at room temperature in a cappedreaction vial was added neat Cs₂CO₃ (34.69 mg, 0.1065 mmol) as a solidfollowed by (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (14.54 μL,0.1065 mmol). The reaction mixture was capped and heated to 80° C. for 4hours. The reaction mixture was cooled to room temperature and dilutedwith 15 mL of ethyl acetate. The organic phase was washed with water andbrine. The combined organic phases were isolated, dried over MgSO₄,filtered and concentrated. The residue was purified over silica gel(10-60% EtOAc in hexanes) to afford6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(11 mg, 47% yield).

Step C: To a stirred suspension of6-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(11 mg, 0.025 mmol) in 500 μL of isopropyl alcohol in a capped flask atroom temperature was added HCl (10 μL, 0.051 mmol, 5M in isopropylalcohol). The reaction mixture was heated to 60° C. for 3 hours. Thereaction mixture was cooled to room temperature, dried under a stream ofnitrogen and then stirred into a mixture of dichloromethane (10 mL) and20% sodium carbonate solution (10 mL). After 5 minutes, the layers wereseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic layers were dried over MgSO₄, filtered andconcentrated. The residue was purified over silica gel (0-10% methanolin CH₂Cl₂) to afford(R)-3-(4-(4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(4 mg, 37% yield) as a white foam. Mass spectrum (apci) m/z=394.2 (M+H).¹H NMR (CDCl₃) δ 8.45 (d, J=0.8 Hz, 1H), 8.25 (s, 1H), 8.21 (s, 1H),8.03 (m, 2H), 7.99 (s, 1H), 6.95 (dd, J=2.5, 1.0 Hz, 1H), 5.01 (q, J=8.0Hz, 1H), 4.35 (d, J=5.3 Hz, 2H), 4.17 (pentet, J=4.9 Hz, 1H), 3.72-3.64(m, 2H), 3.57 (br s, 1H), 2.99-2.85 (m, 2H), 2.62-2.53 (m, 1H), 2.49 (brs, 1H), 2.18 (dq, J=11.3, 8.4 Hz, 1H), 1.67 (m, 1H), 0.91 (d, J=7.0 Hz,3H).

Example 218(S)-1-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol

Step A: To a solution of(R)-4-(1-(1-cyclopropylpropyl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.15 g, 0.45 mmol) [peak B from chiral chromatography in Example 285;chirality arbitrarily assigned] in THF (4 mL) was added 60% sodiumhydride (0.036 g, 0.90 mmol) followed by (S)-2-methyloxirane (0.052 g,0.90 mmol) and the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with water and extractedinto EtOAc. The combined organic phases were washed with brine, driedover MgSO₄ and concentrated in vacuo. The residue was purified oversilica gel (0->100% EtOAc in CH₂Cl₂) to afford crude(S)-1-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol(0.1 g, 55% yield).

Step B: To a solution of(S)-1-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol(0.1 g, 0.3 mmol) in CH₂Cl₂ was added 1H-imidazole (0.03 g, 0.5 mmol)and tert-butylchlorodimethylsilane (0.08 g, 0.5 mmol) and the reactionmixture was stirred overnight at room temperature. The reaction mixturewas washed with HCl (1N), brine, dried over MgSO₄ and concentrated invacuo. The residue was purified over silica gel (0-50% EtOAc/CH₂Cl₂) toafford6-(1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-1H-pyrazol-4-yl)-4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.50 g, 39% yield).

Step C: To a solution of6-(1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-1H-pyrazol-4-yl)-4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(0.050 g, 0.099 mmol) in isopropyl alcohol (10 mL) was added 4 drops ofconcentrated HCl and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated in vacuoand the residue was partitioned between EtOAc and 0.1 M NaOH. Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified over silica gel (0-5%MeOH/CH₂Cl₂) to afford(S)-1-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol(0.015 g, 0.038 mmol, 39% yield). Mass spectrum (apci) m/z=392.2 (M+H).¹H NMR (CDCl₃) δ 8.43 (d, J=1.0 Hz, 1H), 8.24 (s, 1H), 8.23 (s, 1H),8.02 (m, 2H), 7.98 (s, 1H), 6.94 (dd, J=2.3, 1.0 Hz, 1H), 4.32-4.22 (m,2H), 4.08 (m, 1H), 3.40 (m, 1H), 2.21-2.03 (m, 2H), 1.42-1.32 (m, 1H),1.28 (d, J=6.3 Hz, 3H), 0.91 (t, J=7.4 Hz, 3H), 0.82-0.74 (m, 1H),0.62-0.54 (m, 1H), 0.46-0.34 (m, 2H).

1. A compound of the general Formula I

or a stereoisomer or pharmaceutically acceptable salt or solvatethereof, wherein: R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—,(1-4C alkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl, H₂N(1-4Calkoxy)(3-6C)alkyl, Cyc¹(CH₂)_(m)—, hetCyc¹, hetCyc²CH₂—,R^(a)R^(b)NC(═O)CH₂—, hetCyc^(3a)(1-3C)alkyl,hetCyc^(3b)(2-3C)hydroxyalkyl, RCR^(d)N(2-3C)alkyl, (1-3Calkyl)₂NSO₂(2-3C)alkyl, hetCyc⁴, (1-6C)alkyl or CH₃SO₂(1-6C)alkyl; Cyc¹is a 4-6 membered cycloalkyl substituted with 1-2 substituentsindependently selected from the group consisting of HO, HOCH₂—,(1-3C)alkyl, H₂NHC(═O)—, (1-3C alkyl)₂NC(═O)—, and HOCH₂CH₂NHC(═O)—; mis 0 or 1; hetCyc¹ is a 4-6 membered heterocyclic ring having a ringheteroatom selected from N, O and S wherein the S is optionally oxidizedto SO₂, wherein said heterocyclic ring is optionally substituted with asubstituent selected from the group consisting of OH, (1-3Calkyl)C(═O)—, (1-3C alkyl)SO₂—, (1-3C alkyl)NHC(═O)— and NH₂CH₂C(═O)—;hetCyc² is a 4-6 membered heterocyclic ring having a ring S atom,wherein the S is oxidized to SO₂; R^(a) and R^(b) are independently H or(1-3C)alkyl, or R^(a) and R^(b) together with the nitrogen atom to whichthey are attached form a 4-6 membered ring optionally having a ringoxygen atom; hetCyc^(3a) and hetCyc^(3b) are independently a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein said heterocyclic ring is optionallysubstituted with 1-2 substituents independently selected from the groupconsisting of halogen, OH, (1-4C)alkoxy, HOCH₂—, (1-3C alkyl)C(═O)— andoxo; R^(c) is H or (1-3C)alkyl; R^(d) is (1-3C)alkyl, (1-3C alkyl)SO₂—,hetCyc^(a), or (3-6C)cycloalkyl optionally substituted with HOCH₂—;hetCyc^(a) is a 5-6 membered azacyclic ring optionally substituted with1-2 substituents independently selected from oxo and (1-3C)alkyl;hetCyc⁴ is azetidinyl substituted with ((CH₃)₂N)₂P(═O)— or Y—C(═O)—; Yis ReR^(f)N(CH₂)^(n)—, hetCyc^(b)CH₂—, Cyc², hydroxy(1-3C)alkyl, (1-3Calkyl)₂NC(═O)—, (1-3C)alkylSO₂- or (1-3C)alkyl; n is 0 or 1; R^(e) andR^(f) are independently H or (1-3C)alkyl; hetCyc^(b) is a 4-5 memberedazacyclic ring optionally substituted with OH; Cyc² is a(3-6C)cycloalkyl optionally substituted with OH; R² is (1-6C)alkyl,trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl (optionallysubstituted with one or two halogens), (3-6C)cycloalkylCH₂—, HOC(═O)— orphenyl, and R³ is (1-6C)alkyl or (3-6C)cycloalkyl, or R² and R³ togetherwith the carbon atom to which they are attached form a 3-7 memberedcycloalkyl ring optionally substituted with one or two substituentsindependently selected from OH, (1-6C)alkyl and hydroxy(1-6C)alkyl, orR² and R³ together with the carbon atom to which they are attached forma 4-membered saturated azacyclic ring substituted with SO₂CF₃; and R⁴ ishydrogen or (1-6C)alkyl.
 2. (canceled)
 3. A compound according to claim1, wherein R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—, (1-4Calkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl, H₂N(1-4Calkoxy)(3-6C)alkyl, Cyc¹(CH₂)_(m)—, hetCyc¹, hetCyc²CH₂—,RaR^(b)NC(═O)CH₂—, hetCyc^(3a)(1-3C)alkyl,hetCyc^(3b)(2-3C)hydroxyalkyl, R^(c)R^(d)N(2-3C alkyl)-, (1-3Calkyl)₂NSO₂(2-3C alkyl)- or hetCyc⁴.
 4. A compound according to claim 1,wherein R¹ is hydroxy(1-6C)alkyl, HOCH₂(cyclopropylidine)CH₂—, (1-4Calkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl,dihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl or H₂N(1-4Calkoxy)(3-6C)alkyl.
 5. A compound according to claim 1, wherein R¹ isdihydroxy(2-6C)alkyl, H₂N(3-6C)hydroxyalkyl, (1-3Calkyl)NH(3-6C)hydroxyalkyl or (1-3C alkyl)₂N(3-6C)hydroxyalkyl.
 6. Acompound according to claim 1, wherein R¹ is dihydroxy(2-6C)alkyl.
 7. Acompound according to claim 1, wherein R¹ is H₂N(3-6C)hydroxyalkyl,(1-3C alkyl)NH(3-6C)hydroxyalkyl or (1-3C alkyl)₂N(3-6C)hydroxyalkyl. 8.A compound according to claim 1, wherein R² is (1-6C)alkyl,trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl (optionallysubstituted with one or two halogens), (3-6C)cycloalkylCH₂—, HOC(═O)— orphenyl; R³ is (1-6C)alkyl or (3-6C)cycloalkyl; and R⁴ is hydrogen or(1-6C)alkyl.
 9. A compound according to claim 8, wherein: R² is(1-6C)alkyl; R³ is (1-6C)alkyl; and R⁴ is hydrogen.
 10. A compoundaccording to claim 1, wherein: R² and R³ together with the carbon atomto which they are attached form a 3-7 membered cycloalkyl ringoptionally substituted by one or two groups independently selected fromOH, (1-6C)alkyl and hydroxy(1-6C)alkyl; and R⁴ is hydrogen or(1-6C)alkyl.
 11. A compound according to claim 1, wherein: R² and R³together with the carbon atom to which they are attached form a4-membered saturated azacyclic ring substituted with SO₂CF₃; and R⁴ ishydrogen or (1-6C)alkyl.
 12. A compound according to claim 1, selectedfrom4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;4-(1-cycloheptyl-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;4-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)morpholine;4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;N,N-dimethyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)acetamide;1-morpholino-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanone;6-(1-(3-(methylsulfonyl)propyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;5-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)oxazolidin-2-one;N-methyl-N-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide;N,N-dimethyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanamine;4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran1,1-dioxide;N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-amine;3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)thietane1,1-dioxide;(R)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(S)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methanol;(S)-5-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one;(R)-5-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one;3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol;(R)-4-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran1,1-dioxide;6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;N,N-dimethyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanesulfonamide;2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanesulfonamide;4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;4-(1-isopropyl-1H-pyrazol-4-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;(R)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(pyrrolidin-2-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;(S)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(pyrrolidin-2-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;(R)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;(S)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine;1-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;6-(1-(1-methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;2-methoxy-1-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;N-methyl-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxamide;N,N-dimethyl-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxamide;2-amino-1-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;6-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone;N-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxamide;N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxamide;Bis-N,N-dimethyl-P-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)phosphonicamide;2-methyl-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one;cyclopropyl(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone;2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazol-1-yl)butanoicacid;2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)butan-1-ol;2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)propan-1-ol;3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)pentan-1-ol;4-(1-(3-ethyl-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(1-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(3-methylpentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclopentyl)methanol;6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(2-methylcycloheptyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-11H-pyrazol-1-yl)cyclopentanol;(R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-2,3-diol;(R)-3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-2,3-diol;3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(2R,3R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-2,3-diol;2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)propane-1,3-diol;(S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol;4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,3-diol;(R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol;(2S,3S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-2,3-diol;(2R)-3-(4-(4-(1-phenylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(2R)-3-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-(4-(4-(1-((S)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-(4-(4-(1-((R)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-(4-(4-(1-((R)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-(4-(4-(1-((S)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-(4-(4-(1-((R)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(2R)-3-(4-(4-(1-(1-(3,3-difluorocyclobutyl)propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-3-methylbutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(S)-2-(4-(4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(R)-2-(4-(4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(S)-2-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(R)-2-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(S)-3-(4-(4-(1-((S)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-2-(4-(4-(1-(4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(R)-2-(4-(4-(1-(4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(2S,3S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol;(2S,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol;(2R,3S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol;(2R,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,2-diol;(R)-3-(4-(4-(1-((1R,2S)-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((1S,2R)-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S′)-2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;N-isopropyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)acetamide;1-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(R)-1-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(R)-1-(methylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(S)-1-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(S)-1-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(R)-1-(3-methoxyazetidin-1-yl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(S)-1-(3-methoxyazetidin-1-yl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)-3-(pyrrolidin-1-yl)propan-2-ol;(S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)-3-(pyrrolidin-1-yl)propan-2-ol;(R)-1-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(S)-1-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;(S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;4,4,4-trifluoro-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;3,3-dimethyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;(S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;(R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol;2-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;trans-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanol;cis-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol;(1s,3s)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutanol;cis-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclohexanol;((1s,3s)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutyl)methanol;((1r,3r)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclobutyl)methanol;2-methyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(S)-2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine;(R)-2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine;(S)-2-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(R)-2-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(R)-2-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(1R,2S,4s)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-diol;(1R,2S,4r)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-diol;N-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)cyclopropanamine;4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;(R)-6-(1-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;(S)-6-(1-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;6-(1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine;1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)piperidin-4-ol;(R)-1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)pyrrolidin-3-ol;(S)-1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)pyrrolidin-3-ol;(S)-1-methyl-3-((2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)amino)pyrrolidin-2-one;(R)-1-methyl-1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)amino)pyrrolidin-2-one;4-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)piperazin-2-one;(3-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)amino)cyclobutyl)methanol;(1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)methanol;1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)piperazin-2-one;(R)-2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-amine;(S)-2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-amine;2-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(R)-3-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-3-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(1R,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol;(1S,2S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol;(2S,3S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;(2R,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;(2R,3S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;(2S,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;(3S,4R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)tetrahydrofuran-3-ol;(3R,4S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)tetrahydrofuran-3-ol;trans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol;(1s,3s)-1-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol;(1s,3s)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol;(1r,3r)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol;(trans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol;(cis-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol;(1r,3r)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide,(1s,3s)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide;(1r,3r)-N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide;(1s,3s)-N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide;(1r,3r)-N-(2-hydroxyethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide;(1s,3s)-N-(2-hydroxyethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide;(S)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one;2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone;(R)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one;2-hydroxy-2-methyl-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one;(1-hydroxycyclopropyl)(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone;(cis-3-hydroxycyclobutyl)(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone;(trans-3-hydroxycyclobutyl)(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone;2-(3-hydroxyazetidin-1-yl)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone;1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(pyrrolidin-1-yl)ethanone;N,N-dimethyl-2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)acetamide;(S)-3-amino-2-methyl-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol;4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol;1-(4-hydroxy-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanone;2-amino-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone;2-(methylamino)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone;(3R,4R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)piperidin-3-ol;(1S,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol;(1R,2S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclopentanol;2,2-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol;(1-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol;(2R)-3-(4-(4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-1-cyclobutylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-1-cyclobutylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol(S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,3-diol;(R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butane-1,3-diol;(R)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(S)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-1-((S)-2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-1-cyclopropylbutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-1-cyclopropylbutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((1S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((1R,2S)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((R)-1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-2-(4-(4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(S)-2-(4-(4-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(R)-3-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-((S)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-2-(4-(4-(1-(1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol;(R)-3-(4-(4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;(R)-3-(4-(4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol;and(S)-1-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol;and pharmaceutically acceptable salts thereof.
 13. The compoundaccording to claim 12, wherein compound is a trifluoroacetic acid saltor a hydrochloric acid salt.
 14. A pharmaceutical composition, whichcomprises a compound of Formula I as defined in claim 1 or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable diluent or carrier.
 15. A method fortreating a JAK kinase-associated disease or disorder in a subject inneed thereof, which comprises administering to said subject atherapeutically effective amount of a compound of Formula I as definedin claim 1 or a pharmaceutically acceptable salt or solvate thereof. 16.A method for treating an autoimmune disease or inflammatory disease in asubject in need thereof, which comprises administering to said subject atherapeutically effective amount of a compound of Formula I as definedin claim 1 or a pharmaceutically acceptable salt or solvate thereof. 17.The method according to claim 16, wherein the disease or disorder isselected from: (i) arthritis; (ii) intestinal inflammations; (iii)airways diseases; (iv) allergic reactions; (v) eye diseases, disordersor conditions; (yl) skin diseases, conditions or disorders; (vii)sepsis, systemic inflammatory response syndrome, and neutropenic fever;(viii) fibrosis; (ix) gout; (x) lupus and manifestations of lupus; (xi)neurodegenerative diseases; (xii) diabetes and complications fromdiabetes, metabolic syndrome and obesity; (xiii) axialspondyloarthorpathy (axial SpA); and (xiv) Interferon type 1 activationdisorders.
 18. The method of claim 17, wherein the disease or disorderis selected from: (i) arthritis; (ii) intestinal inflammations; (yl)skin diseases; and (x) lupus and manifestations or lupus.
 19. A methodfor treating organ, tissue or cell transplant rejection in a subject inneed thereof, which comprises administering to said subject atherapeutically effective amount of a compound of Formula I as definedin claim 1 or a pharmaceutically acceptable salt or solvate thereof. 20.A method for treating a malignancy in a subject in need thereof, whichcomprises administering to said subject a therapeutically effectiveamount of a compound of Formula I as defined in claim
 1. 21. The methodaccording to claim 15, wherein said compound of Formula I is formulatedfor oral administration.
 22. The method according to claim 21, whereinsaid compound of Formula I is formulated as a tablet or capsule.
 23. Themethod according to claim 15, further comprising administering anadditional therapy or therapeutic agent.
 24. The method according toclaim 23, wherein the additional therapeutic agent is selected from thegroup consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide,deoxyspergualin, mycophenolate, daclizumab, OKT3, AtGam, aspirin,acetaminophen, ibuprofen, naproxen, piroxicam, antiinflammatorysteroids, methotrexate, statins, anti-TNF agents, abatacept,cyclophosphamide, mycophenolic acid, hydroxychloroquine, and metformin.25. The method according to claim 23, wherein the additional therapeuticagent is selected from the group consisting of mitotic inhibitors,alkylating agents, anti-metabolites, antisense DNA or RNA, intercalatingantibiotics, growth factor inhibitors, signal transduction inhibitors,cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators,proteasome inhibitors, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, cytostatic agentsanti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, andprenyl-protein transferase inhibitors.
 26. (canceled)
 27. A method forinhibiting JAK kinase activity in a cell, the method comprisingcontacting the cell with a compound of Formula I as defined in claim 1or a pharmaceutically acceptable salt or solvate thereof.
 28. The methodof claim 27, wherein said contacting is in vitro.
 29. The method ofclaim 27, wherein said contacting is in vivo.
 30. The method accordingto claim 27, wherein the cell is a mammalian cell.
 31. A process for thepreparation of a compound of Formula I or a pharmaceutically acceptablesalt thereof according to claim 1, which comprises: (a) reacting acorresponding compound having the formula II:

where R², R³ and R⁴ is as defined for Formula I, and R^(t) and R^(u) areH or (1-6C)alkyl, or R^(t) and R^(u) together with the atoms to whichthey are connected form a 5-6 membered ring optionally substituted with1-4 substituents selected from (1-3C alkyl), with a correspondingcompound having the formula III

where R¹ is as defined for Formula I and L¹ is halogen, an alkylsulfonate group, an aryl sulfonate group or a triflate group, in thepresence of a palladium catalyst and a base and optionally in thepresence of a ligand; or (b) for a compound of Formula I where R¹ is(1-6C)alkyl, hydroxy(1-6C)alkyl, hetCyc¹, hetCyc²CH₂—,R^(a)R^(b)NC(═O)CH₂—, hetCyc^(3a)(1-3C alkyl)-, R^(c)R^(d)N(2-3Calkyl)-, (1-3C alkyl)₂NSO₂(2-3C alkyl)- or CH₃SO₂(1-6C)alkyl, reacting acorresponding compound having the

where R², R³ and R⁴ are as defined for Formula I, with (1-6C)alkyl-L²,hydroxy(1-6C)alkyl-L², hetCyc¹-L², hetCyc²CH₂-L²,R^(a)R^(b)NC(═O)CH₂-L², hetCyc^(3a)(1-3C alkyl)-L², R^(c)R^(d)N(2-3Calkyl)-L², (1-3C alkyl)₂NSO₂(2-3C alkyl)-L² or CH₃SO₂(1-6C)alkyl-L² andL² is halogen, an alkyl sulfonate group or an aryl sulfonate group, inthe presence of a base, where hetCyc¹, R^(a), R^(b), hdrCyc^(3a), R^(c),and R^(d) are as defined for Formula I; or (c) for a compound of FormulaI where R¹ is dihydroxy(2-6C)alkyl, reacting a reacting a correspondingcompound having the formula IV

where R², R³ and R⁴ are as defined for Formula I, with a compound havingthe formula V, VI or VII

where each R¹ is methyl, R^(v), R^(w) and R^(x) are independently H ormethyl, and L³ is a halogen atom, an alkyl sulfonate group or an arylsulfonate group, in the presence of a base, followed by treatment withhydrochloric acid; or (d) for a compound of Formula I where R¹ isH₂NCH₂CH(OH)CH₂—, reacting a corresponding compound having the formulaVIII

where R², R³ and R⁴ are as defined for Formula I, with a base; or (e)for a compound of Formula I where R¹ is (1-3Calkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl)₂N(3-6C)hydroxyalkyl, orhetCyc^(3b)(2-3C)hydroxyalkyl-, where hetCyc^(3b) is a 4-6 memberedheterocyclic ring having a ring nitrogen atom, wherein said heterocyclicring is optionally substituted with 1-2 substituents independentlyselected from the group consisting of halogen or (1-4C)alkoxy, reactinga corresponding compound having the formula IX

where R², R³ and R⁴ are as defined for Formula I, with a reagent havingthe formula (1-3C alkyl)NH₂, (1-3C alkyl)₂NH or

where R^(y) and R^(z) are independently selected from the groupconsisting of halogen or (1-4C)alkoxy and hetCyc^(3b) is a 4-6 memberedheterocyclic ring having a ring nitrogen atom, wherein said heterocyclicring is optionally substituted with 1-2 substituents independentlyselected from the group consisting of halogen or (1-4C)alkoxy; or (f)for a compound of Formula I where R¹ is hydroxy(1-6C)alkyl,(hydroxy)trifluoro(1-6C)alkyl or (1-4C alkoxy)(1-6C)hydroxyalkyl,reacting a corresponding compound having the formula X

where R², R³ and R⁴ are as defined for Formula I, with a reagent havingthe formula

where G is (1-4C)alkyl, trifluoro(1-4C)alkyl or (1-4Calkoxy)(1-4C)alkyl; or (g) for a compound of Formula I where R¹ is

reacting a corresponding compound having the formula XI

where R², R³ and R⁴ are as defined for Formula I and R^(1a) is

respectively, with a reducing agent; or (h) for a compound of Formula Iwhere R¹ is hydroxy(1-6C)alkyl, reacting a corresponding compoundwherein the hydroxy(1-6C)alkyl is protected as an alkyl ester with abase; or (i) for a compound of Formula I where R¹ isR^(c)R^(d)N(CH₂CH₂)— or hetCyc^(3a)(CH₂CH₂)—, where R^(c), R^(d), andhetCyc^(3a) are as defined for Formula I, reacting a correspondingcompound having the formula XII

where R², R³ and R⁴ are as defined for Formula I and L⁴ is a halogen, analkyl sulfonate group or an aryl sulfonate group, with a reagent havingthe formula RCR^(d)NH₂ or

where hetCyc^(3a) is as defined for Formula I; or (j) for a compound ofFormula I where R¹ is H₂NCH₂CH(OCH₃)CH₂—, reacting a correspondingcompound having the formula XIII

where R², R³ and R⁴ are as defined for Formula I, with hydrazine; or (k)for a compound of Formula I where R¹ is

reacting a corresponding compound having the formula XIV

where R², R³ and R⁴ are as defined for Formula I, with an oxidizingagent; or (l) for a compound of Formula I where R¹ is Cyc¹(CH₂)_(m)—,Cyc¹ is a 4-6 membered cycloalkyl substituted with H₂NHC(═O)— or (1-3Calkyl)₂NC(═O)—, and m is 0, reacting a corresponding compound of FormulaI where R¹ is Cyc¹(CH₂)_(m)—, Cyc¹ is a 4-6 membered cycloalkylsubstituted with CH₃C(═O)O— and m is 0 with ammonia or (1-3C alkyl)NH—;or (m) for a compound of Formula I wherein R² and R³ form a 4-memberedazacyclic ring substituted with SO₂CF₃, and R¹ and R⁴ are as defined forFormula I, reacting a compound having the formula XIV

where R¹ and R⁴ are as defined for Formula I, withtrifluoromethanesulfonic anhydride in the presence of a base; andoptionally removing any protecting groups and optionally preparing apharmaceutically acceptable salt thereof.
 32. A compound according toclaim 12, selected from:

and pharmaceutically acceptable salts thereof.
 33. A compound accordingto claim 1, selected from:

and pharmaceutically acceptable salts thereof.
 34. A compound accordingto claim 12, selected from:

and pharmaceutically acceptable salts thereof.
 35. A compound accordingto claim 12, selected from:

and pharmaceutically acceptable salts thereof.
 36. A compound accordingto claim 12, selected from:


37. A compound according to claim 12, selected from:

and pharmaceutically acceptable salts thereof.
 38. A compound accordingto claim 12, selected from:

and pharmaceutically acceptable salts thereof.